Blood Cancer &
 Leukemia

Leukemia Cancer News September 2004

Protein Expression Predicts Aggressiveness of Chronic Lymphocytic Leukemia

According to a recent article published in The New England Journal of Medicine, levels of expression of the protein ZAP-70 predicts the aggressiveness of chronic lymphocytic leukemia in younger patients and may help to individualize treatment options.

Chronic lymphocytic leukemia (CLL), also referred to as acute lymphoblastic leukemia, is a cancer involving the lymph (immune) system, which includes lymph nodes, blood and blood vessels found throughout the body, as well as the spleen, thymus and tonsils. This cancer is found in high quantities throughout circulating blood and in bone marrow (spongy material inside large bones that produces blood forming cells). CLL is characterized by the production of atypical lymphocytes. Lymphocytes are specialized immune cells, of which there are two types: B and T-cells.

These cells are produced in the bone marrow and each has a very specific function in aiding the body to fight infection. The large majority of CLL cases involve mature B-lymphocytes that tend to live much longer than normal, accumulating in the blood, bone marrow, lymph nodes and spleen. This results in overcrowding of these areas, suppressing the formation and function of blood and immune cells that are normally present. Additionally, the cancerous lymphocytes themselves do not function normally, leading to a further decrease in the ability of the body to fight infection. CLL is considered a slow-growing or low-grade cancer.

Standard treatment options for CLL may include chemotherapy, radiation therapy, biologic therapy, and/or high-dose therapy and stem cell transplantation. Since CLL can be such a slow-growing cancer, treatment may also be delayed until signs of disease progression. Researchers are continuing to evaluate associations between disease characteristics and the aggressiveness of CLL, as some patients can live with the disease for years without treatment or signs of progression, while others benefit from immediate treatment.

One test that has been associated with the aggressiveness of CLL is the expression of part of a gene referred to as an unmutated immunoglobulin heavy-chain variable-region gene (IgVH). However, research is ongoing in order to determine an even more accurate predictor of aggressiveness, so that patients with more aggressive forms of CLL may be treated early with more intense therapy, while patients with less aggressive forms of CLL may be spared unnecessary treatment.

Researchers affiliated with the Chronic Lymphocytic Leukemia Research Consortium recently conducted a clinical study evaluating the expression of a protein referred to as ZAP-70 and its potential relationship to the aggressiveness of CLL. The study included 307 patients with an average age of 52 years who were tested for ZAP-70, as well as mutations in the IgVH gene. In the group of patients who did not express ZAP-70, the time from diagnosis of CLL to initial treatment was 11 years in those with a mutated IgVH gene and 7.1 years in those with an unmutated IgVH gene. In the group of patients who did express ZAP-70, the time from diagnosis of CLL to initial treatment was only 2.8 years for those with an unmutated IgVH gene and 4.2 years for those with a mutated IgVH gene.

The researchers concluded that the expression of ZAP-70 strongly predicts the aggressiveness of CLL, as patients who did not express the protein had a significantly longer period of time between diagnosis and the need for treatment compared to those who did express the protein, regardless of the IgVH status. Patients diagnosed with CLL may wish to speak with their physician about the risks and benefits of being tested for ZAP-70 and how the results may affect their treatment decisions.

Reference: Rassenti LZ, Huynh L, Toy TL, et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. The New England Journal of Medicine. 2004; 351: 893-901.

Stem Cells Find Cancer Metastasis in Animals
Gene Therapy Targets Solid and Blood Tumors

Stem cells that act as seek-and-destroy missiles appear to be able to find cancer wherever it hides - at least in animals, according to M. D. Anderson researchers. This novel approach to gene therapy may have use in a wide variety of solid and blood tumors.

This addresses our great need for cancer gene therapies aimed at curbing the metastatic spread of cancer cells, says Michael Andreeff, M.D., Ph.D., professor in M. D. Andersons Departments of Blood and Marrow Transplantation and Leukemia. It is exciting because it is an entirely new way of thinking about gene therapy and not just a twist on an old idea.

Repairing tissue

Andreeff presented the concept and a series of supporting animal studies at the annual meeting of the American Association for Cancer Research (AACR) in April.

The novel strategy takes advantage of the fact that tumors attract a certain kind of stem cell, mesenchymal progenitor cells (MSC), which act as the body's natural tissue repair system.
These unspecialized cells migrate to an injury by responding to signals from the area, and there they develop the kind of connective tissue needed to repair the wound.

But they also respond to tumors often characterized as never healing wounds which call the stem cells to help build up normal tissue needed to support the cancer, Andreeff says.

Andreeff and a team of researchers removed a small number of MSC from the bone marrow, expanded them in the laboratory, and genetically altered the stem cells with a variety of therapeutic genes. When intravenously injected into tumor-bearing mice, the millions of engineered stem cells engraft in the cancer and activate their genetic payload, which then attacks the cancer.

Hope for several cancers

Andreeff presented animal data suggesting that gene-modified MSC can inhibit the growth of leukemias, lung metastases of melanomas and breast cancer, ovarian and brain tumors. For example, MSC gene therapy cured 70% of mice implanted with one kind of human ovarian cancer. So far, researchers delivered interferon alpha and beta, and an oncolytic (tumor-destroying) virus into the tumors.

"This drug delivery system is attracted to cancers, both primary and metastatic, and anti-tumor effects are observed when the cells integrate into the tumor microenvironment, Andreeff says. The most important discovery here is that these cells are capable of migrating from the bone marrow or blood circulation selectively into tumors and produce anti-tumor agents only at the sites of these tumors and their metastasis.

Contact: Bill Schaller
[email protected]
617-632-5357
Dana-Farber Cancer Institute

Optimizing protein's 'death domain' halts leukemia in laboratory study

Spiral-shaped molecules, reinforced by chemical 'staples,' could aid drug discovery

BOSTON-2-Sep-2004-A part of the system that causes cells to self-destruct when they are damaged or unneeded has been harnessed to kill leukemia cells in mice, say scientists at the Dana-Farber Cancer Institute. The discovery could aid in the discovery of new drugs for cancer and other diseases.
The researchers plucked a critical "death domain" from a key molecule in the self-destruction mechanism of a cell, stiffened its Slinky-like structure with chemical "staples," and used it as a highly specific weapon to destroy leukemia cells. The findings will be published in the Sept. 3 issue of the journal Science.

"We have demonstrated an approach for getting at potential new drugs by using natural sequences [of amino acids] that have known biological effects," says Stanley J. Korsmeyer, MD, of Dana-Farber, co-senior author of the paper. "In this case we took the critical killer domain out of a pro-death molecule and chemically reinforced it, so we were able to get it into cancer cells and kill them."

Loren D. Walensky, MD, PhD, of Dana-Farber and Children's Hospital Boston is the paper's first author and Gregory L. Verdine, PhD, of Harvard University, is co- senior author.

Korsmeyer and his colleagues have pioneered studies of apoptosis, or programmed cell death, that rids the body of damaged or unneeded cells. Apoptosis is directed by a complex collection of proteins in a yin-yang-like balance and is activated by a variety of external and internal signals. Some of the proteins set in motion a cell's death, while other "survival" proteins act to prevent programmed cell death.

One hallmark of cancer is that an excess of anti-death or survival proteins overwhelms the system when it is trying shut down the abnormal cell, causing the cell to reproduce, dangerously out of control, when it should be dying.

The pro-death part of the apoptosis toolbox includes a number of molecules known as BH3-only proteins. To ensure that cells destroy themselves when appropriate, despite contrary signals from anti-death molecules, BH3-only proteins contain a peptide subunit, termed "BH3", that is made of amino acids and functions as a critical "death domain." This subunit forms a coiled structure called an "alpha helix," which is similar to the shape of a Slinky toy. Amino acids positioned on the surface of the coils bind to amino acids on anti-death molecules such as BCL-2 and inhibit their activity. BCL-2, a key part of the apopotosis mechanism, was discovered by Korsmeyer.

Building on other recent work, Walensky sought to remove the alpha-helical BH3 subunit from the protein and use it as a sharply aimed tool to shut down the BCL-2 protein and activate the death pathway in cancer cells, without harming normal cells. If that proved successful, it would show that the BH3 alpha helix and alpha helices from many other proteins could be used like keys to turn off protein activity involved in disease processes.

These alpha helices then could serve as the foundation for building novel drugs. But one hurdle loomed. When the helical "death domain" is removed from its parent protein, it loses its rigid shape, becoming floppy liked an overstretched Slinky. In this form, it is vulnerable to degradation, unable to enter cells, and left powerless to block the antideath BCL-2 protein. Walensky's goal was to return the isolated amino acid helix to its original shape after its removal from the BH3-containing protein.

Drawing on his dual background in chemistry and cell biology, and applying a strategy developed by Verdine, who is a chemist, Walensky found the answer. First, he made synthetic amino acids that mimicked some of those within the helix. "Then we swapped out the natural amino acids and inserted the synthetic ones" at certain positions along the helix. Crucially, the artificial amino acids were linked to each other by a pair of hydrocarbon subunits. Like a reinforcing metal staple, Walensky explains, these links held the peptide in its natural coiled configuration.

Further experiments confirmed that the stapled BH3 alpha helix retained its biological activity. In fact, it bound even more strongly to its target on the BCL-2 molecule, blocking its activity. Moreover, the reinforced coil was able to enter cancer cells and trigger apoptosis, or self-destruction, of those cells.

The most dramatic success occurred in mice transplanted with leukemia cells that gave off a glow when the mice were injected with a light-emitting substance, luciferin. After they administered the reinforced BH3 alpha helices, scientists noted that the glowing regions representing the leukemia cells retreated as the cells died, and the treated mice survived longer than those that were untreated.

"By applying a new chemical approach, we were able to brace peptides from within to generate biological tools that hadn't existed before," says Walensky, "and these new molecules directly inhibit a protein interaction that we're interested in. The potential is that you could take any alpha helix involved in a pivotal protein interaction, relevant to cancer or other diseases, and target it to that protein to disrupt the disease process."

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The research was supported by grants from the National Institutes of Health, the Lymphoma Research Foundation, the American Society of Hematology and the Lauri Strauss Leukemia Foundation.

Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.

Environment May Be Linked to Rising Leukemia

Mon Sep 6, 9:54 AM ET Health - Reuters

By Patricia Reaney

LONDON (Reuters) - Pesticides or chemicals in the environment may be behind the steady rise in cases of childhood leukemia, which have increased five-fold since the early 1900s, scientists said on Monday.

Fewer children actually die from the blood cancer than 40-50 years ago but cases have increased about one percent per year in the last half century.

"It represents a five-fold increase," Professor Michel Coleman of the London School of Hygiene and Tropical Medicine told a conference delving into the causes of the increase.

From about 10 cases per million population in England and Wales in 1911-1915, cases rose to about 46 per million at the end of the century.

"The evidence suggests a steady increase in the occurrence of leukemia in this country and in others," said Coleman.

Leukemia is the most common childhood cancer, accounting for nearly one-third of all cases. Most of the rise is in children aged 1 to 4.

Boys have about a 10 percent higher risk of developing the disease, according to Coleman.

Professor Denis Henshaw of the University of Bristol in south-western England and chairman of the conference, said a possible cause could be environmental agents or chemicals that were not around 50 years ago.

Children are thought to be predisposed to the illness at birth by something that occurs in the womb but they do not develop it unless it is triggered by causes as yet unknown.

Ionising radiation, electromagnetic fields, viruses, infections and chemicals and pesticides are thought to be possible triggers.

Professor Alan Preece, also from the University of Bristol, presented research showing the unborn child is particularly sensitive to the effects of exposure to such agents.

In laboratory and animal studies, Preece found levels of such compounds were higher in the fetus than in the placenta or the mother.

"The environmental agents cross the placenta and accumulate in certain foetal organs, varying according to the nature of the agent," Preece said.

"The exact levels are as yet unknown but we know that childhood leukemia is initiated in utero and this could well be a factor in the initiation."

More than 200 doctors and specialists are attending the week-long meeting, organized by Children with Leukemia, Britain's leading charity devoted to conquering the illness.

Night Light Suspected in Rise in Child Leukemia

Wed Sep 8, 2004 05:39 AM ET

By Patricia Reaney
LONDON (Reuters) - A growing body of evidence linking increased night light to certain types of cancer has led researchers to suspect it could be connected to the steady increase in cases of childhood leukemia.

Scientists presenting research at the First International Scientific Conference on Childhood Leukemia on Wednesday said that light at night (LAN) and working shifts, which disrupts the body's internal clock, have been associated with an raised risk of breast and colorectal cancer.

"We don't know whether abnormal light exposure is generating this higher incidence of childhood leukemia or not, but in view of what we know of other forms of cancer this is not unreasonable," Russell Foster, a molecular neuroscientist at Imperial College London, said in an interview.

"It is something we should look at and pay attention to." Leukemia, the commonest cancer in young children, is thought to result from a mixture of genetic predisposition and environmental factors.

Ionizing radiation, electromagnetic fields, chemicals and viruses and infections have been implicated in the incidence of the illness, which has increased by about 50 percent in children under five years old since the 1950s.

"This is a potential environmental factor that we should take more seriously," Foster said.

Professor Russel Reiter, of the University of Texas, said that compared to 100 years ago people are exposed to much more light at night, which disrupts the body's circadian rhythms, or internal clock, and suppresses the normal nocturnal production of the hormone melatonin.

Studies have shown that a reduction in melatonin is linked to an increased risk of certain cancers.

"As an antioxidant, in many studies melatonin has been shown to protect DNA from oxidative damage. Once damaged, DNA may mutate and carcinogenesis may occur," Reiter told the meeting.

Foster, who discovered a new type of light-sensing cell within the eye that provides information that regulates the circadian system, said there is a known link between the timing of anti-cancer drugs in children with leukemia and the risk of relapse.

"There is a big effect in giving the drug at the right time," he told Reuters. He also noted that genes and protein products that are associated with the circadian system also seem to interact closely with the cell cycle and the proliferation of cells. Cancer develops when damaged cells duplicate uncontrollably and form tumors.

"The potential is there that when we disturb our circadian rhythms, when we suppress our melatonin, that increased cancer risk can result," said Reiter.

"Misuse of light may be contributing to a number of different cancers including the increasing incidence of leukemia in children," he added.

08-Sep-2004

Component in Green Tea Helps Kill Leukemia Cells

Theres increasing evidence that green tea offers health benefits. Recent studies have reported that polyphenols, compounds found in green tea, may offer protection against certain cancers and may aid in the destruction of cancer cells.

Newswise Theres increasing evidence that green tea offers health benefits, reports the September issue of Mayo Clinic Womens HealthSource. Recent studies have reported that polyphenols, compounds found in green tea, may offer protection against certain cancers and may aid in the destruction of cancer cells.

Now, Mayo Clinic researchers have found that another component in green tea helps kill the most common form of leukemia in the United States. The component, known as epigallocatechin-3-gallate, kills leukemia cells by interrupting some of the communication signals they need to survive. Researchers studied cells taken from patients who have B-cell chronic lymphocytic leukemia, a noncurable form of the disease.

The studys findings are a step toward more effective or easily tolerated therapies to prevent the disease from progressing. And, while its too early to recommend green tea to prevent or treat leukemia, drinking it is unlikely to cause health problems.

Mayo Clinic Womens HealthSource is published monthly to help women enjoy healthier, more productive lives. Revenue from subscriptions is used to support medical research at Mayo Clinic. To subscribe, please call 800-876-8633, extension 9PK1.

Turmeric May Protect Against Leukemia -Scientist

Sep 9, 2004
LONDON (Reuters) - Turmeric, a spice used extensively in Asia as a key ingredient of curry, may be protecting children against leukemia, a scientist said on Thursday.
Rates of the blood cancer have been rising steadily for the past 50 years but its incidence in Asia is much lower than in the West.

Professor Moolky Nagabhushan, of the Loyola University Medical Center in Chicago, told a conference that factor could be due, at least partly, to turmeric.

"Some of the known risk factors that contribute to the high incidence of childhood leukemia are the interaction of many lifestyle and environmental factors," he said.

Scientists suspect some children are born with a predisposition to the illness, which occurs most often in children aged 1-4, but that they do not develop the disease unless it is triggered by environmental factors.

Infections, viruses, radiation, pesticides and chemicals are among the suspected culprits.

"Our studies show that turmeric -- and its coloring ... curcumin -- in the diet mitigate the effects of some of these risk factors," Nagabhushan added.

He and his colleagues showed that the spice irreversibly inhibits the multiplication of leukemia cells in laboratory studies and seems to protect against damage caused by cigarette smoke and eating certain processed foods.

Dr Marilyn Kwan, of the University of California, Berkeley, presented separate results of a study of more than 300 children which showed the benefits of eating healthy foods.

"We found that regular consumption of oranges and/or bananas during the first two years of life was associated with a reduced risk of childhood leukemia," Kwan said.

"These findings are consistent with the protective role of fruits and vegetables observed in adult cancers," she added.

Oranges are rich in vitamin C and bananas have high levels of potassium, both of which are thought to protect against cancer.

The week-long childhood leukemia conference is organized by the British charity Children with Leukemia.

2004-09-09

A New Protein Is Discovered To Play A Key Role In Cancer Progression

NEW YORK, September 9, 2004 - Many cancers, including colon, prostate, and leukemia, continue to grow unchecked because they do not respond to a signal to die and stop proliferating from Transforming Growth Factor-beta (TGF-b). The cause of this signaling disruption of the normal cell cycle has not been fully understood. For the first time, scientists at Memorial Sloan-Kettering Cancer Center have discovered the biologic function of the cytoplasmic form of the Promyelocytic Leukemia protein (PML), and identified it as an essential factor in maintaining TGF-b signaling. Their findings, published in the September 9 issue of the journal Nature, explain the link between these two proteins in the development of cancer and suggest that restoring their activity may provide a possible cancer treatment.

Research Points In New Direction For Cancer Clues

Findings Offer Clue To How Molecule Can Both Stimulate, Suppress Cell Growth

"Through our discovery of the biologic function of PML and its essential role in maintaining TGF-b signaling, we can better understand the progression of many human cancers," said Pier Paolo Pandolfi, M.D., Ph.D., Head of the Molecular and Developmental Biology Laboratory at Memorial Sloan-Kettering and the study's senior author. "Restoring PML function may correct this signaling defect therefore providing a novel therapeutic target for cancer drugs."

TGF-b is a protein that can suppress tumor development by signaling a cell to stop growing. The unresponsiveness to TGF-b signaling has been associated with a variety of human cancers. In addition to this loss of TGF-b, loss of PML is associated with tumor progression in many human cancers, including prostate, breast, colon, and lung, as shown by Dr. Pandolfi and colleagues in a recently published study in the Journal of the National Cancer Institute. In a later work published in Nature Cell Biology, they also demonstrated an unexpected role for PML in affecting the nucleolar network for tumor suppression and in regulating the function of a gene crucial to the suppression of the genesis of cancer.

In this current work, the Sloan-Kettering researchers found that cytoplasmic PML (cPML) also has a key role in cancer development. It is required for the formation of a signaling complex that is an essential factor in activating TGF-b signaling necessary to suppress the growth of cancer cells. When cPML is lost, TGF-b signaling is disrupted. Primary cells from Pml-null mice are resistant to TGF-b dependent growth arrest, induction of aging (cellular senescence), and cell death (apoptosis). However, when PML function is added back to these cells, this defect is corrected and TGF-induced activity restores normal cell functions.

"The study found an unexpected role of cPML which highlights the importance of analyzing the status of PML in human cancers," said Hui-Kuan Lin, Ph.D., of the Molecular and Developmental Biology Laboratory at Memorial Sloan-Kettering and the study's first author.

Stephan Bergmann, Ph.D., of the Molecular and Developmental Biology Laboratory at Memorial Sloan-Kettering contributed to this work and the Nature Cell Biology research. The study was supported, in part, by grants from the National Institutes of Health.

Memorial Sloan-Kettering Cancer Center is the world's oldest and largest institution devoted to prevention, patient care, research and education in cancer. Our scientists and clinicians generate innovative approaches to better understand, diagnose and treat cancer. Our specialists are leaders in biomedical research and in translating the latest research to advance the standard of cancer care worldwide.

This story has been adapted from a news release issued by Memorial Sloan-Kettering Cancer Center.

Roche and SGX Enter New Anti-Viral Drug Discovery Partnership

BASEL, Switzerland and SAN DIEGO, Sept. 9 /PRNewswire/ -- Roche and SGX (Structural GenomiX) today announced an alliance to discover new anti-viral therapeutics. Using its proprietary FAST(TM) technology, SGX will be responsible for discovering small molecule inhibitors for Roche to develop and commercialize worldwide. SGX will receive an upfront payment, research funding and milestone payments as product candidates advance through development, and royalties on product sales.

"We seek partners that will help build our pipeline in areas of strategic focus," said Peter Hug, Roche's Global Head of Pharma Partnering. "SGX will be generating new anti-viral leads for Roche, further strengthening our commitment to developing novel medicines in virology."

"This partnership with Roche is consistent with our integrated business strategy," added Dr. Stephen K. Burley, SGX's Chief Scientific Officer, "which is to apply FAST(TM) to generate novel lead candidates in key therapeutic areas for strategic partners, as well as oncology candidates for further development by SGX."

About SGX

SGX is a biotechnology company focused on the discovery and development of innovative therapeutics. SGX's lead product candidate is Troxatyl®, a Phase 1/2 novel cancer therapeutic that has shown promise in Acute Myelogenous Leukemia and other malignancies including blast phase Chronic Myelogenous Leukemia and various solid tumors. SGX has developed a preclinical pipeline leveraging FAST(TM) lead generation, a proprietary fragment-based approach to identify novel drug candidates that capitalizes on SGX core expertise in high-throughput protein crystallography, state of the art computational chemistry and automated parallel synthesis. SGX has secured revenue generating drug discovery and development partnerships with leading pharmaceutical and biotechnology companies including Eli Lilly, Serono S.A. and Roche. For more information, please visit the company's website at www.stromix.com.

The future of leukemia treatment

9/11/2004
By: Ivanhoe Broadcast News

Researchers say about 500 children are diagnosed with acute myeloid leukemia each year. Acute promyelocytic leukemia (APL) is a subtype of the cancer acute myeloid leukemia (AML). It accounts for about 1 percent of all childhood leukemia cases. The disease is characterized by an abnormal form of white blood cells. These abnormal blood cells in the bone marrow and peripheral blood replace normal blood cells.

APL is most often found in children between ages 2 years and 3 years, and in adults over age 40. However, it has also been found in older children and teenagers. APL is more common among children of Hispanic and Mediterranean origin.

Early diagnosis of APL is important because patients may develop serious blood-clotting or bleeding problems. This can usually be prevented or treated by giving patients blood thinner medications. Other treatments might include transfusions of platelets or other blood products. With modern therapies, bleeding is often less of a problem once treatment of APL begins.

Standard treatment for APL patients includes chemotherapy along with an oral form of vitamin A known as ATRA. With this treatment, about 75 percent to 80 percent of APL patients are expected to survive. Side effects of the combined treatment include breathing problems due to lung fluid buildup, low blood pressure, kidney damage and severe fluid retention.

Researchers from the M.D. Anderson Cancer Center in Houston are studying a new, chemotherapy-free alternative for patients with APL. The treatment uses a form of ATRA, known as lipoATRA. LipoATRA is simply ATRA wrapped in fat and injected. Researchers tested the therapy on 34 patients. It won't work for everyone, but results show lipoATRA kept 10 of the 34 patients in remission for several years without having to undergo chemotherapy. The remaining patients who did not respond as well to the lipoATRA treatment had to undergo chemotherapy. There are still side effects with lipoATRA and they may not be any better than side effects seen with chemotherapy.

The treatment is not yet approved by the FDA, and researchers say it does not offer any practical benefits at this time for patients with APL. However, they say their study is significant because it demonstrates how the future of leukemia will be treated.

"It's, I think, probably the first demonstration in the field of leukemia that you can cure patients without giving them chemotherapy. It's plausible to defer chemotherapy and still wind up okay," Elihu Estey, M.D., said.

For more information, contact

Elihu Estey, M.D
The University of Texas
M.D. Anderson Cancer Center
1515 Holcombe Blvd.
Unit 428
Houston, TX 77030-4009

Oranges, bananas and turmeric prevent leukemia

September 16, 2004

ISLAMABAD, September 17 (Online): Giving infants oranges and bananas regularly may halve their risk of developing childhood leukemia, suggest the results of a new study.

And a diet containing the curry spice turmeric may also be protective - accounting for the differences in childhood leukemia rates between east and west - says a leading scientist.

Children who ate oranges, orange juice or bananas between four to six times a week during their first two years of life had a significantly reduced risk of developing the cancer, revealed the observational study by US researchers.

Previous studies on childhood leukaemias have not examined the effects of the overall diet in this way, focusing more on possible risk foods like cured meats.

"Our study is unique, and we have elucidated a significant protective association with the consumption of oranges, bananas and orange juice," says Marilyn Kwan, an epidemiologist at the University of California, Berkeley.

However, she cautions that without carrying out a randomised controlled trial, it is difficult to predict exactly how protective eating these fruits may be, or to make firm public health recommendations. But she notes that in her study "there was a 50 per cent reduction in risk".

The evidence for oranges and bananas, and turmeric in preventing leukaemia was presented at Children with Leukaemia's international leukaemia conference in London, UK, on Thursday.

Oranges and bananas may protect against childhood leukemia because they are a rich source of vitamin C, which is an antioxidant. They could act by reducing oxidative DNA damage, and so stop the initiation of cancerous processes.

Bananas are also rich in potassium. Animal studies have indicated that potassium stabilises DNA and can reduce rates of mutation

Afraid that cancer will return, doctors treat "cure'' like a four-letter word

MARILYNN MARCHIONE, AP Medical Writer
September 18, 2004

There wasn't any doubt six years ago that Doug Jensen had cancer. The Oregon engineer's blood was clogged with the immature cells that are sure signs of leukemia. Treatment with a new wonder drug, Gleevec, made them disappear.

Since then, doctors repeatedly have searched his blood, even individual molecules, for bits of DNA and other substances that would reveal he still had the disease. None has been found. Is he cured? "They don't use that word," said Jensen, who would dearly love to hear it.

Ironically, at a time when more people are cured of cancer than ever before, fewer doctors seem willing to say so. They call the cancer undetectable, or in remission. They tell patients they can quit seeing cancer specialists. They quote statistics and say chances are slim that the disease will come back.

They say these things because the simple truth is, they can't tell when or if someone has been cured. Even the most widely used benchmark -- being alive five years after diagnosis -- has no real basis in science, experts admit.

There's a label for people like Jensen who are in cancer limbo -- "survivor."

Some wear it with pride, having fought the enemy and lived to tell about it. Others think it drafts them into a club to which they don't want to belong -- Veterans of Forever Wars.

Nearly 10 million Americans have battled cancer, including 1.4 million who had it more than 20 years ago and are called "long-term survivors" by those afraid to call them cured.

Their ranks include Lance Armstrong, who heads a survivorship foundation and boasts of beating testicular cancer that had spread to his lungs and brain. Can he ever be declared cured, or must he always carry "survivor" with his Tour de France titles?

"The medical community has backed off the term 'cured,"' said Julia Rowland, a psychologist who directs the federal Office of Cancer Survivorship, which was started in 1996, the year Armstrong began treatment.

The reasons involve more than just semantics, she and others say. Cure is a term with emotional and medical meanings about which there is little agreement.

To many people, it means that the cancer is gone and is not going to come back.

But some cancers -- certain lymphomas and leukemias in particular -- never go away completely yet are controlled so that they're no longer life-threatening. Some call that a remission, but others consider it a cure.

Other cancers look like they've gone away -- no signs of them can be found by exquisitely sensitive and sophisticated tests -- but recur many years later, suggesting that they weren't really cured after all. Breast cancer is notorious for this.

"What today does 'cure' really mean?" asked Dr. Len Lichtenfeld, deputy chief medical officer of the American Cancer Society. "Does that mean there's no cancer cells in your body from this cancer any more, or does that mean that at this particular time, there's only 2, 3, 4 5 percent chances it's going to come back?"

He's not the only one trying to define the concept.

"It's something we've had discussions about internally," said Diane Balma, public policy director for the Susan G. Komen Breast Cancer Foundation, which calls its fund-raiser Race for the Cure, not Race for the Remission.

She is distrustful of absolutes. Diagnosed with breast cancer at age 30 but with no sign of it nearly a decade later, "I will never consider myself cured," she said. "Cure means there's no possibility of recurrence, and that's why I don't like the word. We all know there's a possibility of recurrence."

Ellen Stovall, who had Hodgkin's disease and now heads an advocacy group, the National Coalition for Cancer Survivorship, tries to ignore the issue.

"Cure is a term that I don't need to have in order to fell well and healthy," she said. "It's a word without meaning in some respects. It may be useful for testifying before Congress or getting a job," but it doesn't predict future health.

When doctors do declare someone cured, how can they tell?

In the past, it was when they could cut out a tumor and surrounding tissue until no more abnormal cells could be seen. Many doctors today are willing to call testicular, prostate and certain other kinds of cancer cured if the tumors are small and confined to a gland or organ that can be removed.

But Dr. David Carbone, a lung cancer expert at the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., would be reluctant to say that about the type of cancer he treats.

"All the time, I see patients who had surgery done and the surgeon says they got it all, they're cured. Statistically, they may have a good chance of being cured. But it's all a probability. Has that surgeon done them a favor by saying that?"

The opposite situation also is true: Doctors sometimes declare a cancer cured even after it had spread beyond the place it originated. This used to be considered an inevitably terminal condition, but it's often conquered now with chemotherapy, radiation and other treatments.

Still, it's much harder to predict someone's ultimate survival after cancer has spread. Doctors look at factors like how aggressive a tumor is and where and how quickly it traveled, but not all patients get such tests. Most of the time, only time will tell.

"Some of these people have long-term survival, and some of them are going to be cured of their disease. We don't know what to tell them," Lichtenfeld said.

Which is why many doctors turn to statistics, and five-year survival is their favorite. By that measure, cancer surely is being cured: Nearly two out of three patients make it to that point today; only half did 25 years ago.

However, there is nothing magical about that benchmark. Survival is a continuum, and five years is no more meaningful a dividing point than two, three, six or nine years.

"I honestly don't know where that came from. It goes back a long time," said Rowland at the federal cancer agency. She and others think it grew from a need to have some way of measuring survival and tracking cancer trends in the overall population.

More relevant statistics take into account the type of cancer someone has. With some, like bladder cancer and many of the blood and bone marrow malignancies, if someone is alive after a year or two, their long-term outlook is pretty good. But much to the chagrin of breast cancer advocacy groups and people with the deadly skin cancer melanoma, five-year survival doesn't bring great assurance that those diseases won't come back years later.

Dr. David Johnson, deputy director of Vanderbilt-Ingram Cancer Center and president of the American Society of Clinical Oncology, thinks the five-year benchmark became balm for doctors and patients who found the unpredictability of their situations intolerable.

"Physicians were reluctant to say 'you might recur,' so they'd use these terms like 'OK, in five years, you'll be cured,"' he said.

Johnson and his colleague, Carbone, both have survived lymphoma and are past the five-year mark. But statistics only tell what happens to the masses, not to individual patients.

"They can't be half-cured, like they can't be half-pregnant. So a lot of time discussing percentages often isn't productive," Johnson said.

"You're either cured or you're not," Carbone agreed.

Complicating matters is the risk of second cancers. Some of the very treatments used to cure cancer, like chemotherapy and radiation, actually can trigger new cancers down the road. People with an inherited genetic flaw that predisposed them to cancer still have that underlying problem after being treated successfully.

"The fact that you've had cancer once means that you can get it again," Johnson said.

But some of the trickiest situations today involve people like Jensen. Average survival for his form of cancer, chronic myelogenous leukemia, was only five years until 2001, when Gleevec, one of a new generation of drugs that more precisely target cancer, came on the market.

More than 95 percent of CML patients do stunningly well on Gleevec, "but this may be more akin to controlling diabetes with insulin than curing diabetes," said Dr. Brian Druker, the Oregon Health & Science University cancer specialist who pioneered the drug's development.

"When we look at our patients with extremely sensitive techniques, we can still see leukemia cells," he said. "Our concern is that if we stop Gleevec, then their leukemia will come back. Are they cured? Probably not. Are they well controlled? Absolutely, yes."

Jensen is one of the few CML patients who show absolutely no sign of cancer. He has taken Gleevec since 1999, when he enrolled in an experiment that still provides him the drug for free. It doesn't make him sick because it attacks the root causes of his cancer without killing healthy cells.

He feels like he could take it forever, and wants to. But he and his doctors are considering taking him off.

"I honestly don't know what the right thing to do is," but stopping the drug is the only way to find out if he and others like him are cured, Druker said.

"That's a little scary, I have to admit. Everything's going along so well," Jensen said. But he talked it over with his wife and decided that if Druker and his other doctors ask him to, he'd probably go off the drug.

"They say it's undetectable," he said of his cancer. "I'd like to have them say I'm cured."

Cancer Dies When 'Defect' Fixed

Sept. 20, 2004

"Abnormalities in genes affecting [programmed cell death] have been found in nearly every cancer, suggesting they may be necessary to develop cancer."
Researcher Anthony Letai

(WebMD) Fixing a defect in cancer cells makes them die a natural death, a study in mice shows. The finding means that a series of new anticancer drugs already in development are likely to work. They may work very well indeed, the study suggests.

When normal cells reach the end of their useful life, they self-destruct. This suicide process is called programmed cell death or apoptosis. But cancer cells have a defective self-destruct program. They make too much of a molecule called BCL-2, which gobbles up the chemical messengers that activate cell suicide.

Anthony Letai, MD, PhD, Stanley Korsmeyer, MD, and colleagues at Dana-Farber Cancer Institute wondered what would happen if they stripped cancer cells of their BCL-2 armor.

"What better way to kill cancer cells than targeting the molecules that directly control their survival?" Letai asks in a news release.

To see what would happen if cancer cells didn't have BCL-2 protection, the researchers created a strain of genetically engineered mice whose BCL-2 could be switched off by a common antibiotic. The mice also carried a gene that gave them leukemia.

By the age of 7 weeks, all 28 test animals had leukemia. All 14 mice that continued making BCL-2 died of leukemia by 100 days of age. But the 14 treated animals, who received the antibiotic in drinking water, had their BCL-2 cut off. All of them had fewer leukemia cells, and their white blood cells numbers became normal within days of therapy. Five of these mice lived for more than 200 days, and one lived for more than a year.

That's exciting news. Until this experiment, nobody was sure that simply removing the barrier to cell suicide would result in cancer-cell death.

"Abnormalities in genes affecting [programmed cell death] have been found in nearly every cancer, suggesting they may be necessary to develop cancer," Letai and colleagues write in the September 2004 issue of Cancer Cell.

Several drug companies are working on treatments that would block BCL-2. BCL-2 is crucial for proper immune function. But the mouse studies suggest that humans could tolerate a temporary BCL-2 block long enough for such future drugs to have an anticancer effect.

Senior study author Korsmeyer serves on the scientific advisory board of IDUN Pharmaceuticals, which is developing cell-death therapeutics.

SOURCES: Letai, A. Cancer Cell, September 2004; vol 6: pp 241-245. News release, Dana-Farber Cancer Institute, Boston.

By Daniel J. DeNoon
Reviewed by Brunilda Nazario, MD

ZIOPHARM Presents Data on New Class of Arsenic Compounds at International Leukemia Meeting

NEW HAVEN, Conn., Sept. 20 /PRNewswire/ -- ZIOPHARM today announced that Dr. Srdan Verstovsek, MD, and his colleagues at The University of Texas M. D. Anderson Cancer Center reported mouse study data on the company's lead compound, ZIO-101, showing they were able to increase the arsenic dose 30- to-50-fold over that of inorganic arsenic without experiencing any severe side effects. Further testing with ZIO-101 in dogs showed no evidence of heart damage or other severe toxicity.

The findings were presented at the seventh annual meeting of New Trends in the Treatment of Acute Leukemia, September 11-14 in Dubrovnic. The conference addressed recent developments and progress in treating the disease and included both US and European experts. One of the highlights of the meeting was the presentation on ZIO-101, the first in a class of new organic arsenicals.

Currently, inorganic arsenic therapy has been shown to be highly effective in treating a rare form of leukemia called acute promyelocytic leukemia (APL). However, physicians have been impeded in using inorganic arsenic at higher doses to treat other blood cancers and much more common solid cancers because of the risk of damage to the heart and other serious toxicities from increasing the dose of inorganic arsenic.

The M. D. Anderson team also presented laboratory data that suggests ZIO-101 kills cancer cells more effectively than inorganic arsenic by using different mechanisms. The Company has targeted a late 1Q 2005 starting date for phase I study in hematological cancer and a second study shortly thereafter for solid tumors.

About ZIOPHARM
ZIOPHARM, Inc. is a privately held company. It was founded in January 2004 to develop and commercialize a diverse, risk-sensitive portfolio of in-licensed cancer therapies. All products are focused on addressing unmet medical needs, with the potential for expedited approval and broad usage.

ZIOPHARM's first in-licensed product, ZIO-101, is a small molecule from The University of Texas M. D. Anderson Cancer Center and is planned for Phase I study initiating late in 1Q-2005. The company anticipates licensing of ZIO-201 by 4Q-2004.

ZIOPHARM is actively evaluating and negotiating for additional product candidates with the objective of a balanced portfolio of at least three clinical-stage compounds and at least one late preclinical candidate by the end of 2005. Each product candidate undergoes a tightly managed evaluation process leveraging the company's management team's combined 100+ years of oncology experience in clinical development, regulatory strategy, business development and product commercialization.

Both ZIOPHARM's structure and mission set it apart from other cancer drug companies. The company's rigorously disciplined approach to screening product candidates is designed to accelerate clinical programs while reducing the expense and risk typically incurred in researching, developing and launching new cancer products. With an intimate understanding of the regulatory approval process, the company expects to break new ground as regards to speed and efficiency as it brings new cancer compounds to market.

CONTACT: ZIOPHARM, Inc., IR/Media Relations, +1-203-848-3414

Maxim swoons after cancer drug flunks key trial

Company will continue to explore uses for Ceplene
By Terri Somers
UNION-TRIBUNE STAFF WRITER
September 21, 2004

Maxim Pharmaceuticals shares dived almost 50 percent yesterday after the San Diego biotechnology company said its drug Ceplene failed to increase survival rates in a critical trial with advanced skin cancer patients.

The company had aimed to win U.S. and European approvals to market the drug for patients with malignant melanoma that has metastasized to the liver. Maxim already had received U.S. approval to provide Ceplene as an experimental treatment to critically ill melanoma patients, even though the drug was still being tested.

But the trial results make it unlikely the drug will receive the final approvals the company had hoped for, Maxim chief executive Larry Stambaugh said.

Maxim shares were down $2.90, or 49 percent to $3.04 at the close of Nasdaq Stock Market yesterday, a new one-year low.

The trial was a "must-do" for the company to get approval for Ceplene, and the failure represents a "major setback," Merriman Curhan Ford & Co. analyst Kate Winkler wrote in a report. Winkler lowered her rating on the company's shares to "sell" from "buy."

But despite the setback, Stambaugh said the 12 years and millions of dollars the company has spent developing the drug are not lost.

In May the company reported that when used on patients with leukemia, a combination of Ceplene and interleukin-2, a common cancer treatment, produced a statistically significant improvement in leukemia-free survival.

"We had intended to file for regulatory approval (to treat) leukemia second, after we received melanoma approval," Stambaugh said. "Treatment of leukemia will now move up to first."

The company is also testing the drug in treating kidney, intestinal and colorectal cancers.

The latest Phase 3 trial on patients with malignant melanoma, the most deadly form of skin cancer, was not the first with disappointing results.

In 2000, the FDA rejected Ceplene for treating melanoma based on another Phase 3 trial. The company went back to work on the drug and hoped this trial would produce better results.

The company submitted an application in November seeking European marketing approval for the use of Ceplene as a treatment for malignant melanoma. It had hoped to win that approval by the end of the year.

The company does not plan to immediately scrap all its plans for the drug's use on melanoma, Stambaugh said.

"It's too early to make that decision," he said. "We haven't reviewed all the data."

"We are perplexed," he said. "After several trials it showed promise in this very tough cancer. We'll have to see if it is still possible we could learn something that will allow us to work with melanoma, which has become the fastest growing cancer without any effective treatment."

In addition to Winkler, other analysts also lowered their ratings on Maxim's stock. Rodman & Renshaw lowered Maxim's shares from market perform to market underperform. Earlier in the year the company had rated Maxim market outperform.

Handelsbanken Capital Markets downgraded Maxim from a buy to a sell.

Benzene Linked to Childhood Leukemia

French Study Associates Disease With Gas Stations, Auto Repair Shops

By Miranda Hitti
WebMD Medical News Reviewed By Brunilda Nazario, MD

Aug. 18, 2004 -- Living next door to a gas station or auto repair shop may be associated with an increased risk of childhood leukemia, according to a new French study.

The problem might stem from exposure to benzene emitted by gas stations and auto repair businesses, write the researchers in the journal Occupational and Environmental Medicine. Previous studies have shown a clear association between the occupational exposure to benzene and acute leukemia in adults.

The association in children "could be due to chance, although the strength of the association and the duration trend are arguments for causal association," write the researchers.

The team of 11 scientists studied 280 children with acute leukemia and 285 children with other health problems at hospitals in four French cities: Nancy, Lille, Lyon, and Paris.

Of the children with leukemia, 40 had acute non-lymphocytic leukemia.

Acute lymphocytic leukemia is the most common type of leukemia in childhood and the most common type of childhood cancer in developed countries, but few risk factors have been identified for the disease.

More Exposure, More Risk

In the study, data were collected during face-to-face interviews with the children's mothers, asking specific questions about their career histories and where they lived during their pregnancies and after their children were born.

The researchers wanted to find out if the mothers' jobs they had while pregnant or homes were near high-traffic roads or adjacent to benzene emission sources like gas stations and auto repair shops.

There was no clear association between the mother's job during pregnancy and leukemia. Residential traffic density was also not associated with leukemia.

However, living next door to a gas station or car repair garage during childhood was associated with the risk of childhood leukemia.

Only a small number of children in the study were exposed to neighboring repair shops and gas stations. Still, there was significant trend in exposure duration among them, write the researchers. The longer a child lived by a gas station or car repair garage, the higher their risk seemed to be.

The association was particularly strong for acute non-lymphocytic leukemia, with 10% of cases found among children living near auto repair shops or gas stations.

The results held after screening out other possible risk factors, but they need confirmation by further studies, say the researchers.

Salmedix, Inc. Announces the Initiation of Two New Clinical Trials

BIOWIRE2K

SAN DIEGO--(BUSINESS WIRE)--Sept. 30, 2004--
A New Phase II Study of SDX-101 for Chronic Lymphocytic Leukemia, and a Cooperative Group Study of SDX-102 for Brain Cancer

Salmedix, Inc. announced today the initiation of two new clinical studies. A new Phase II clinical study of SDX-101, or R-etodolac, for patients with Chronic Lymphocytic Leukemia ("CLL") has begun enrolling patients in Sweden, Germany and the UK, and is expected to begin enrolling in France and Poland in the near future. This study is an open-label, randomized Phase II clinical trial in which 80 patients with CLL will receive a standard chlorambucil regimen alone or in combination with SDX-101 for multiple cycles. Response rate, using standardized response criteria, will be the primary endpoint. Duration of response will also be evaluated.

"In this new study, we are investigating the utility of SDX-101 in combination with chlorambucil, which is currently one of the regimens used as frontline therapy in CLL patients," stated Pratik Multani, MD, VP of clinical development for the company. "The study is based on data from a previous clinical trial of SDX-101 as a single agent which was presented at the 2003 American Society of Hematology annual meeting by Dr. Markus Jensen from the University of Cologne, Germany. In that dose escalation study in patients with CLL, a total of 43 patients in groups of six to eight were treated twice daily with increasing doses of SDX-101 for up to eight weeks. This prior trial demonstrated clinical activity with an acceptable safety profile. A greater than 25% reduction in absolute lymphocyte count, or ALC, was observed in 73% of patients receiving SDX-101 at doses equal to or greater than 1000 mg twice per day. The maximal ALC decline averaged 48% and typically occurred within four weeks of starting treatment. Following cessation of SDX-101 therapy, ALC generally returned to pre-treatment values. The company believes that this return to pre-treatment values suggests the need for longer duration therapy or use of SDX-101 in combination with other agents active in CLL. In this prior eight-week study, SDX-101 was generally well tolerated with the majority of adverse events defined as mild or moderate, defined as Grade 1 or 2."

On September 17, 2004, a Phase I/II clinical study of SDX-102, or l-alanosine, in patients with previously treated brain tumors was initiated by the New Approaches to Brain Tumor Therapy, or NABTT, a consortium funded by the National Cancer Institute. As the sponsor of the trial, Salmedix is providing clinical supplies of SDX-102 and will be responsible for regulatory filings. NABTT will conduct this trial independently under a standard clinical trial research agreement.

Salmedix has another Phase II trial under way with SDX-102 in advanced stage patients with non-small cell lung cancer, pancreatic cancer, mesothelioma, soft tissue sarcoma and osteosarcoma who have generally failed one or two prior drug regimens.

About Salmedix, Inc.

Salmedix is an oncology drug development company with a commercial focus on the treatment of hematologic malignancies, or blood cancers, with three clinical-stage product candidates, Treanda(TM), SDX-101 and SDX-102. Salmedix maintains its corporate headquarters in San Diego, California.

Forward-Looking Statements

Salmedix cautions you that statements included in this press release that are not a description of historical facts may be forward-looking statements. The inclusion of forward-looking statements should not be regarded as a representation by Salmedix that any of its plans will be achieved. Forward-looking statements include statements related to the ability to enroll the patient numbers required for each trial, that future clinical trial results will support prior findings, or that such future clinical trial results will support regulatory approvals required to market a commercial drug. Actual results may differ materially from those set forth in this release due to the risks and uncertainties inherent in Salmedix's business including, without limitation, difficulties or delays in development, testing, obtaining regulatory approval, producing and marketing its products, unexpected adverse side effects or inadequate therapeutic efficacy of its products that could delay or prevent product development or commercialization, or that could result in recalls or product liability claims, the scope and validity of patent protection for its products, competition from other companies, and its ability to obtain additional financing to support its operations. All forward-looking statements are qualified in their entirety by this cautionary statement, as well as the factors disclosed in the Company's filings with the U.S. Securities and Exchange Commission. Salmedix undertakes no obligation to revise or update this news release to reflect events or circumstances after the date hereof.

New Drug Treatments Offer Hope to Leukemia Patients

By Dennis Thompson
HealthDay Reporter

TUESDAY, Sept. 28 (HealthDayNews) -- Scientists call them "molecularly targeted" drugs, and they represent a remarkable gain in the war against blood cancers.

Leukemia, lymphoma and myeloma are some of the rarest yet most deadly forms of cancer. They account for only 2 percent to 3 percent of all cancers, but cause 10 percent of all cancer deaths, said Alan Kinniburgh, vice president of research for the Leukemia & Lymphoma Society.

These so-called "liquid cancers" cannot be surgically removed and up until recently have been treated with radiation and chemotherapy.

But promising new therapies all involve "molecularly targeted" drugs that disrupt the spread of cancer by honing in on specific mechanical processes that cancer cells to grow.

These breakthrough treatments merit attention in September, which is Leukemia & Lymphoma Awareness Month.

Kinniburgh foresees a day when these new drugs will work together to halt blood cancers, "all hitting the same target, but hitting the target in different ways so the target can't escape being killed."

An estimated 106,000 Americans were diagnosed with leukemia, lymphoma or myeloma last year, according to estimates by the National Cancer Institute (news - web sites). Another 57,500 people died from one of the diseases.

The diseases each begin with one damaged cell that turns cancerous, explained Hildy Dillon, vice president of patient services for the Leukemia & Lymphoma Society.

"They are usually the result of an acquired genetic injury to the DNA of a single cell, which then becomes malignant and starts to reproduce," Dillon said.

The blood cancers interfere with the production of healthy blood cells, Dillon said.

If red blood cells are affected, the person initially suffers from anemia and fatigue. If white blood cells are stricken, the patient initially suffers a high risk of infection. And since the cancers affect blood's ability to clot, patients also suffer unexplained bruises.

If left untreated -- or detected too late -- the blood cancers will kill.

The biggest recent leukemia breakthrough involved the drug Gleevec, which inhibits an enzyme that pushes cells to reproduce uncontrollably. The drug, which gained U.S. Food and Drug Administration (news - web sites) approval in 2001, has been stunningly successful in treating people with chronic myeloid leukemia, often returning patients' blood cell counts to near normal within three or four weeks.

Building on the success of Gleevec are three other new therapies that hold promise, Kinniburgh said.

The first involves clofarabine, a drug that disrupts DNA replication in cancer cells. The drug has been found in clinical trials to put about one-quarter of acute lymphoblastic leukemia (ALL) patients and acute myeloid leukemia (AML) patients into remission when other treatments have failed, Kinniburgh said.

"That provides extra time for a patient to undergo a bone marrow or stem-cell transplant," he said. "That's going to save children's lives." The drug is awaiting FDA (news - web sites) approval.

Another set of drugs undergoing clinical trials are FLT-3 inhibitors, which can disrupt cellular communications that spur cancer growth. Again, about one-quarter of patients with acute myeloid leukemia respond to the drugs, but those who do respond show an 80 percent to 90 percent reduction of cancer cells in the blood, Kinniburgh said.

The third drug, which Kinniburgh calls "Son of Gleevec," is an ABL-kinase inhibitor that targets cancer cell mutations that escape treatment with Gleevec. The drug, BMS-354825, is being tested in patients with chronic myelogenous leukemia whose bodies are resistant to Gleevec.

Doctors generally don't know what causes blood cancers. Benzene, smoking, radiation and the Epstein-Barr virus have all been linked to the diseases, but most of the time physicians have no idea why a specific person has contracted a blood cancer.

"Most often, there really isn't a known cause," Dillon said. "These are not diseases that can be prevented."

There also are multiple types of each of the diseases, which can make it tough for doctors to know how to proceed, Dillon said.

"The challenge is to determine the type of blood cancer a person has because the treatments are designed very specifically," she said. "They're beginning to be able to really target the specific mechanics of each of these different types of cancer.

Leukemia involves cancer of the bone marrow and blood cells, and strikes about 30,600 Americans each year. Another 21,900 die from the disease annually.

Lymphomas are malignancies of the lymphocites, a type of white blood cell. This is the most common blood cancer, afflicting 61,000 people a year and killing 24,700.

Myeloma affects the plasma cells, or white blood cells found primarily in the bone marrow. About 14,600 people are diagnosed with this disease each year, and another 10,900 die.

Leukemia has a five-year survival rate of 44 percent. Lymphoma has a 52 percent survival rate, and myeloma has a 28 percent survival rate.

Kinniburgh said all of the new drug treatments could ultimately be used in concert to specifically target different blood cancers, no matter how rare or obscure.

"With several of these agents hitting each other's cross-resistance, it's certainly very likely we may be able to treat all patients without radiation or chemotherapy," he said. "At some point the goal and the dream would be the drugs could be withdrawn from the patients and they would go on in remission."

More information

To learn more about blood cancers, visit the Leukemia & Lymphoma Society.

Protein Expression Predicts Aggressiveness of Chronic Lymphocytic Leukemia

According to a recent article published in The New England Journal of Medicine, levels of expression of the protein ZAP-70 predicts the aggressiveness of chronic lymphocytic leukemia in younger patients and may help to individualize treatment options.

Chronic lymphocytic leukemia (CLL), also referred to as acute lymphoblastic leukemia, is a cancer involving the lymph (immune) system, which includes lymph nodes, blood and blood vessels found throughout the body, as well as the spleen, thymus and tonsils. This cancer is found in high quantities throughout circulating blood and in bone marrow (spongy material inside large bones that produces blood forming cells). CLL is characterized by the production of atypical lymphocytes. Lymphocytes are specialized immune cells, of which there are two types: B and T-cells.

These cells are produced in the bone marrow and each has a very specific function in aiding the body to fight infection. The large majority of CLL cases involve mature B-lymphocytes that tend to live much longer than normal, accumulating in the blood, bone marrow, lymph nodes and spleen. This results in overcrowding of these areas, suppressing the formation and function of blood and immune cells that are normally present. Additionally, the cancerous lymphocytes themselves do not function normally, leading to a further decrease in the ability of the body to fight infection. CLL is considered a slow-growing or low-grade cancer.

Standard treatment options for CLL may include chemotherapy, radiation therapy, biologic therapy, and/or high-dose therapy and stem cell transplantation. Since CLL can be such a slow-growing cancer, treatment may also be delayed until signs of disease progression. Researchers are continuing to evaluate associations between disease characteristics and the aggressiveness of CLL, as some patients can live with the disease for years without treatment or signs of progression, while others benefit from immediate treatment.

One test that has been associated with the aggressiveness of CLL is the expression of part of a gene referred to as an unmutated immunoglobulin heavy-chain variable-region gene (IgVH). However, research is ongoing in order to determine an even more accurate predictor of aggressiveness, so that patients with more aggressive forms of CLL may be treated early with more intense therapy, while patients with less aggressive forms of CLL may be spared unnecessary treatment.

Researchers affiliated with the Chronic Lymphocytic Leukemia Research Consortium recently conducted a clinical study evaluating the expression of a protein referred to as ZAP-70 and its potential relationship to the aggressiveness of CLL. The study included 307 patients with an average age of 52 years who were tested for ZAP-70, as well as mutations in the IgVH gene. In the group of patients who did not express ZAP-70, the time from diagnosis of CLL to initial treatment was 11 years in those with a mutated IgVH gene and 7.1 years in those with an unmutated IgVH gene. In the group of patients who did express ZAP-70, the time from diagnosis of CLL to initial treatment was only 2.8 years for those with an unmutated IgVH gene and 4.2 years for those with a mutated IgVH gene.

The researchers concluded that the expression of ZAP-70 strongly predicts the aggressiveness of CLL, as patients who did not express the protein had a significantly longer period of time between diagnosis and the need for treatment compared to those who did express the protein, regardless of the IgVH status. Patients diagnosed with CLL may wish to speak with their physician about the risks and benefits of being tested for ZAP-70 and how the results may affect their treatment decisions.

Reference: Rassenti LZ, Huynh L, Toy TL, et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. The New England Journal of Medicine. 2004; 351: 893-901.

Stem Cells Find Cancer Metastasis in Animals
Gene Therapy Targets Solid and Blood Tumors

Stem cells that act as seek-and-destroy missiles appear to be able to find cancer wherever it hides - at least in animals, according to M. D. Anderson researchers. This novel approach to gene therapy may have use in a wide variety of solid and blood tumors.

This addresses our great need for cancer gene therapies aimed at curbing the metastatic spread of cancer cells, says Michael Andreeff, M.D., Ph.D., professor in M. D. Andersons Departments of Blood and Marrow Transplantation and Leukemia. It is exciting because it is an entirely new way of thinking about gene therapy and not just a twist on an old idea.

Repairing tissue

Andreeff presented the concept and a series of supporting animal studies at the annual meeting of the American Association for Cancer Research (AACR) in April.

The novel strategy takes advantage of the fact that tumors attract a certain kind of stem cell, mesenchymal progenitor cells (MSC), which act as the body's natural tissue repair system.
These unspecialized cells migrate to an injury by responding to signals from the area, and there they develop the kind of connective tissue needed to repair the wound.

But they also respond to tumors often characterized as never healing wounds which call the stem cells to help build up normal tissue needed to support the cancer, Andreeff says.

Andreeff and a team of researchers removed a small number of MSC from the bone marrow, expanded them in the laboratory, and genetically altered the stem cells with a variety of therapeutic genes. When intravenously injected into tumor-bearing mice, the millions of engineered stem cells engraft in the cancer and activate their genetic payload, which then attacks the cancer.

Hope for several cancers

Andreeff presented animal data suggesting that gene-modified MSC can inhibit the growth of leukemias, lung metastases of melanomas and breast cancer, ovarian and brain tumors. For example, MSC gene therapy cured 70% of mice implanted with one kind of human ovarian cancer. So far, researchers delivered interferon alpha and beta, and an oncolytic (tumor-destroying) virus into the tumors.

"This drug delivery system is attracted to cancers, both primary and metastatic, and anti-tumor effects are observed when the cells integrate into the tumor microenvironment, Andreeff says. The most important discovery here is that these cells are capable of migrating from the bone marrow or blood circulation selectively into tumors and produce anti-tumor agents only at the sites of these tumors and their metastasis.

Contact: Bill Schaller
[email protected]
617-632-5357
Dana-Farber Cancer Institute

Optimizing protein's 'death domain' halts leukemia in laboratory study

Spiral-shaped molecules, reinforced by chemical 'staples,' could aid drug discovery

BOSTON-2-Sep-2004-A part of the system that causes cells to self-destruct when they are damaged or unneeded has been harnessed to kill leukemia cells in mice, say scientists at the Dana-Farber Cancer Institute. The discovery could aid in the discovery of new drugs for cancer and other diseases.
The researchers plucked a critical "death domain" from a key molecule in the self-destruction mechanism of a cell, stiffened its Slinky-like structure with chemical "staples," and used it as a highly specific weapon to destroy leukemia cells. The findings will be published in the Sept. 3 issue of the journal Science.

"We have demonstrated an approach for getting at potential new drugs by using natural sequences [of amino acids] that have known biological effects," says Stanley J. Korsmeyer, MD, of Dana-Farber, co-senior author of the paper. "In this case we took the critical killer domain out of a pro-death molecule and chemically reinforced it, so we were able to get it into cancer cells and kill them."

Loren D. Walensky, MD, PhD, of Dana-Farber and Children's Hospital Boston is the paper's first author and Gregory L. Verdine, PhD, of Harvard University, is co- senior author.

Korsmeyer and his colleagues have pioneered studies of apoptosis, or programmed cell death, that rids the body of damaged or unneeded cells. Apoptosis is directed by a complex collection of proteins in a yin-yang-like balance and is activated by a variety of external and internal signals. Some of the proteins set in motion a cell's death, while other "survival" proteins act to prevent programmed cell death.

One hallmark of cancer is that an excess of anti-death or survival proteins overwhelms the system when it is trying shut down the abnormal cell, causing the cell to reproduce, dangerously out of control, when it should be dying.

The pro-death part of the apoptosis toolbox includes a number of molecules known as BH3-only proteins. To ensure that cells destroy themselves when appropriate, despite contrary signals from anti-death molecules, BH3-only proteins contain a peptide subunit, termed "BH3", that is made of amino acids and functions as a critical "death domain." This subunit forms a coiled structure called an "alpha helix," which is similar to the shape of a Slinky toy. Amino acids positioned on the surface of the coils bind to amino acids on anti-death molecules such as BCL-2 and inhibit their activity. BCL-2, a key part of the apopotosis mechanism, was discovered by Korsmeyer.

Building on other recent work, Walensky sought to remove the alpha-helical BH3 subunit from the protein and use it as a sharply aimed tool to shut down the BCL-2 protein and activate the death pathway in cancer cells, without harming normal cells. If that proved successful, it would show that the BH3 alpha helix and alpha helices from many other proteins could be used like keys to turn off protein activity involved in disease processes.

These alpha helices then could serve as the foundation for building novel drugs. But one hurdle loomed. When the helical "death domain" is removed from its parent protein, it loses its rigid shape, becoming floppy liked an overstretched Slinky. In this form, it is vulnerable to degradation, unable to enter cells, and left powerless to block the antideath BCL-2 protein. Walensky's goal was to return the isolated amino acid helix to its original shape after its removal from the BH3-containing protein.

Drawing on his dual background in chemistry and cell biology, and applying a strategy developed by Verdine, who is a chemist, Walensky found the answer. First, he made synthetic amino acids that mimicked some of those within the helix. "Then we swapped out the natural amino acids and inserted the synthetic ones" at certain positions along the helix. Crucially, the artificial amino acids were linked to each other by a pair of hydrocarbon subunits. Like a reinforcing metal staple, Walensky explains, these links held the peptide in its natural coiled configuration.

Further experiments confirmed that the stapled BH3 alpha helix retained its biological activity. In fact, it bound even more strongly to its target on the BCL-2 molecule, blocking its activity. Moreover, the reinforced coil was able to enter cancer cells and trigger apoptosis, or self-destruction, of those cells.

The most dramatic success occurred in mice transplanted with leukemia cells that gave off a glow when the mice were injected with a light-emitting substance, luciferin. After they administered the reinforced BH3 alpha helices, scientists noted that the glowing regions representing the leukemia cells retreated as the cells died, and the treated mice survived longer than those that were untreated.

"By applying a new chemical approach, we were able to brace peptides from within to generate biological tools that hadn't existed before," says Walensky, "and these new molecules directly inhibit a protein interaction that we're interested in. The potential is that you could take any alpha helix involved in a pivotal protein interaction, relevant to cancer or other diseases, and target it to that protein to disrupt the disease process."

###
The research was supported by grants from the National Institutes of Health, the Lymphoma Research Foundation, the American Society of Hematology and the Lauri Strauss Leukemia Foundation.

Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.

Environment May Be Linked to Rising Leukemia

Mon Sep 6, 9:54 AM ET Health - Reuters

By Patricia Reaney

LONDON (Reuters) - Pesticides or chemicals in the environment may be behind the steady rise in cases of childhood leukemia, which have increased five-fold since the early 1900s, scientists said on Monday.

Fewer children actually die from the blood cancer than 40-50 years ago but cases have increased about one percent per year in the last half century.

"It represents a five-fold increase," Professor Michel Coleman of the London School of Hygiene and Tropical Medicine told a conference delving into the causes of the increase.

From about 10 cases per million population in England and Wales in 1911-1915, cases rose to about 46 per million at the end of the century.

"The evidence suggests a steady increase in the occurrence of leukemia in this country and in others," said Coleman.

Leukemia is the most common childhood cancer, accounting for nearly one-third of all cases. Most of the rise is in children aged 1 to 4.

Boys have about a 10 percent higher risk of developing the disease, according to Coleman.

Professor Denis Henshaw of the University of Bristol in south-western England and chairman of the conference, said a possible cause could be environmental agents or chemicals that were not around 50 years ago.

Children are thought to be predisposed to the illness at birth by something that occurs in the womb but they do not develop it unless it is triggered by causes as yet unknown.

Ionising radiation, electromagnetic fields, viruses, infections and chemicals and pesticides are thought to be possible triggers.

Professor Alan Preece, also from the University of Bristol, presented research showing the unborn child is particularly sensitive to the effects of exposure to such agents.

In laboratory and animal studies, Preece found levels of such compounds were higher in the fetus than in the placenta or the mother.

"The environmental agents cross the placenta and accumulate in certain foetal organs, varying according to the nature of the agent," Preece said.

"The exact levels are as yet unknown but we know that childhood leukemia is initiated in utero and this could well be a factor in the initiation."

More than 200 doctors and specialists are attending the week-long meeting, organized by Children with Leukemia, Britain's leading charity devoted to conquering the illness.

Night Light Suspected in Rise in Child Leukemia

Wed Sep 8, 2004 05:39 AM ET

By Patricia Reaney
LONDON (Reuters) - A growing body of evidence linking increased night light to certain types of cancer has led researchers to suspect it could be connected to the steady increase in cases of childhood leukemia.

Scientists presenting research at the First International Scientific Conference on Childhood Leukemia on Wednesday said that light at night (LAN) and working shifts, which disrupts the body's internal clock, have been associated with an raised risk of breast and colorectal cancer.

"We don't know whether abnormal light exposure is generating this higher incidence of childhood leukemia or not, but in view of what we know of other forms of cancer this is not unreasonable," Russell Foster, a molecular neuroscientist at Imperial College London, said in an interview.

"It is something we should look at and pay attention to." Leukemia, the commonest cancer in young children, is thought to result from a mixture of genetic predisposition and environmental factors.

Ionizing radiation, electromagnetic fields, chemicals and viruses and infections have been implicated in the incidence of the illness, which has increased by about 50 percent in children under five years old since the 1950s.

"This is a potential environmental factor that we should take more seriously," Foster said.

Professor Russel Reiter, of the University of Texas, said that compared to 100 years ago people are exposed to much more light at night, which disrupts the body's circadian rhythms, or internal clock, and suppresses the normal nocturnal production of the hormone melatonin.

Studies have shown that a reduction in melatonin is linked to an increased risk of certain cancers.

"As an antioxidant, in many studies melatonin has been shown to protect DNA from oxidative damage. Once damaged, DNA may mutate and carcinogenesis may occur," Reiter told the meeting.

Foster, who discovered a new type of light-sensing cell within the eye that provides information that regulates the circadian system, said there is a known link between the timing of anti-cancer drugs in children with leukemia and the risk of relapse.

"There is a big effect in giving the drug at the right time," he told Reuters. He also noted that genes and protein products that are associated with the circadian system also seem to interact closely with the cell cycle and the proliferation of cells. Cancer develops when damaged cells duplicate uncontrollably and form tumors.

"The potential is there that when we disturb our circadian rhythms, when we suppress our melatonin, that increased cancer risk can result," said Reiter.

"Misuse of light may be contributing to a number of different cancers including the increasing incidence of leukemia in children," he added.

08-Sep-2004

Component in Green Tea Helps Kill Leukemia Cells

Theres increasing evidence that green tea offers health benefits. Recent studies have reported that polyphenols, compounds found in green tea, may offer protection against certain cancers and may aid in the destruction of cancer cells.

Newswise Theres increasing evidence that green tea offers health benefits, reports the September issue of Mayo Clinic Womens HealthSource. Recent studies have reported that polyphenols, compounds found in green tea, may offer protection against certain cancers and may aid in the destruction of cancer cells.

Now, Mayo Clinic researchers have found that another component in green tea helps kill the most common form of leukemia in the United States. The component, known as epigallocatechin-3-gallate, kills leukemia cells by interrupting some of the communication signals they need to survive. Researchers studied cells taken from patients who have B-cell chronic lymphocytic leukemia, a noncurable form of the disease.

The studys findings are a step toward more effective or easily tolerated therapies to prevent the disease from progressing. And, while its too early to recommend green tea to prevent or treat leukemia, drinking it is unlikely to cause health problems.

Mayo Clinic Womens HealthSource is published monthly to help women enjoy healthier, more productive lives. Revenue from subscriptions is used to support medical research at Mayo Clinic. To subscribe, please call 800-876-8633, extension 9PK1.

Turmeric May Protect Against Leukemia -Scientist

Sep 9, 2004
LONDON (Reuters) - Turmeric, a spice used extensively in Asia as a key ingredient of curry, may be protecting children against leukemia, a scientist said on Thursday.
Rates of the blood cancer have been rising steadily for the past 50 years but its incidence in Asia is much lower than in the West.

Professor Moolky Nagabhushan, of the Loyola University Medical Center in Chicago, told a conference that factor could be due, at least partly, to turmeric.

"Some of the known risk factors that contribute to the high incidence of childhood leukemia are the interaction of many lifestyle and environmental factors," he said.

Scientists suspect some children are born with a predisposition to the illness, which occurs most often in children aged 1-4, but that they do not develop the disease unless it is triggered by environmental factors.

Infections, viruses, radiation, pesticides and chemicals are among the suspected culprits.

"Our studies show that turmeric -- and its coloring ... curcumin -- in the diet mitigate the effects of some of these risk factors," Nagabhushan added.

He and his colleagues showed that the spice irreversibly inhibits the multiplication of leukemia cells in laboratory studies and seems to protect against damage caused by cigarette smoke and eating certain processed foods.

Dr Marilyn Kwan, of the University of California, Berkeley, presented separate results of a study of more than 300 children which showed the benefits of eating healthy foods.

"We found that regular consumption of oranges and/or bananas during the first two years of life was associated with a reduced risk of childhood leukemia," Kwan said.

"These findings are consistent with the protective role of fruits and vegetables observed in adult cancers," she added.

Oranges are rich in vitamin C and bananas have high levels of potassium, both of which are thought to protect against cancer.

The week-long childhood leukemia conference is organized by the British charity Children with Leukemia.

2004-09-09

A New Protein Is Discovered To Play A Key Role In Cancer Progression

NEW YORK, September 9, 2004 - Many cancers, including colon, prostate, and leukemia, continue to grow unchecked because they do not respond to a signal to die and stop proliferating from Transforming Growth Factor-beta (TGF-b). The cause of this signaling disruption of the normal cell cycle has not been fully understood. For the first time, scientists at Memorial Sloan-Kettering Cancer Center have discovered the biologic function of the cytoplasmic form of the Promyelocytic Leukemia protein (PML), and identified it as an essential factor in maintaining TGF-b signaling. Their findings, published in the September 9 issue of the journal Nature, explain the link between these two proteins in the development of cancer and suggest that restoring their activity may provide a possible cancer treatment.

Research Points In New Direction For Cancer Clues

Findings Offer Clue To How Molecule Can Both Stimulate, Suppress Cell Growth

"Through our discovery of the biologic function of PML and its essential role in maintaining TGF-b signaling, we can better understand the progression of many human cancers," said Pier Paolo Pandolfi, M.D., Ph.D., Head of the Molecular and Developmental Biology Laboratory at Memorial Sloan-Kettering and the study's senior author. "Restoring PML function may correct this signaling defect therefore providing a novel therapeutic target for cancer drugs."

TGF-b is a protein that can suppress tumor development by signaling a cell to stop growing. The unresponsiveness to TGF-b signaling has been associated with a variety of human cancers. In addition to this loss of TGF-b, loss of PML is associated with tumor progression in many human cancers, including prostate, breast, colon, and lung, as shown by Dr. Pandolfi and colleagues in a recently published study in the Journal of the National Cancer Institute. In a later work published in Nature Cell Biology, they also demonstrated an unexpected role for PML in affecting the nucleolar network for tumor suppression and in regulating the function of a gene crucial to the suppression of the genesis of cancer.

In this current work, the Sloan-Kettering researchers found that cytoplasmic PML (cPML) also has a key role in cancer development. It is required for the formation of a signaling complex that is an essential factor in activating TGF-b signaling necessary to suppress the growth of cancer cells. When cPML is lost, TGF-b signaling is disrupted. Primary cells from Pml-null mice are resistant to TGF-b dependent growth arrest, induction of aging (cellular senescence), and cell death (apoptosis). However, when PML function is added back to these cells, this defect is corrected and TGF-induced activity restores normal cell functions.

"The study found an unexpected role of cPML which highlights the importance of analyzing the status of PML in human cancers," said Hui-Kuan Lin, Ph.D., of the Molecular and Developmental Biology Laboratory at Memorial Sloan-Kettering and the study's first author.

Stephan Bergmann, Ph.D., of the Molecular and Developmental Biology Laboratory at Memorial Sloan-Kettering contributed to this work and the Nature Cell Biology research. The study was supported, in part, by grants from the National Institutes of Health.

Memorial Sloan-Kettering Cancer Center is the world's oldest and largest institution devoted to prevention, patient care, research and education in cancer. Our scientists and clinicians generate innovative approaches to better understand, diagnose and treat cancer. Our specialists are leaders in biomedical research and in translating the latest research to advance the standard of cancer care worldwide.

This story has been adapted from a news release issued by Memorial Sloan-Kettering Cancer Center.

Roche and SGX Enter New Anti-Viral Drug Discovery Partnership

BASEL, Switzerland and SAN DIEGO, Sept. 9 /PRNewswire/ -- Roche and SGX (Structural GenomiX) today announced an alliance to discover new anti-viral therapeutics. Using its proprietary FAST(TM) technology, SGX will be responsible for discovering small molecule inhibitors for Roche to develop and commercialize worldwide. SGX will receive an upfront payment, research funding and milestone payments as product candidates advance through development, and royalties on product sales.

"We seek partners that will help build our pipeline in areas of strategic focus," said Peter Hug, Roche's Global Head of Pharma Partnering. "SGX will be generating new anti-viral leads for Roche, further strengthening our commitment to developing novel medicines in virology."

"This partnership with Roche is consistent with our integrated business strategy," added Dr. Stephen K. Burley, SGX's Chief Scientific Officer, "which is to apply FAST(TM) to generate novel lead candidates in key therapeutic areas for strategic partners, as well as oncology candidates for further development by SGX."

About SGX

SGX is a biotechnology company focused on the discovery and development of innovative therapeutics. SGX's lead product candidate is Troxatyl®, a Phase 1/2 novel cancer therapeutic that has shown promise in Acute Myelogenous Leukemia and other malignancies including blast phase Chronic Myelogenous Leukemia and various solid tumors. SGX has developed a preclinical pipeline leveraging FAST(TM) lead generation, a proprietary fragment-based approach to identify novel drug candidates that capitalizes on SGX core expertise in high-throughput protein crystallography, state of the art computational chemistry and automated parallel synthesis. SGX has secured revenue generating drug discovery and development partnerships with leading pharmaceutical and biotechnology companies including Eli Lilly, Serono S.A. and Roche. For more information, please visit the company's website at www.stromix.com.

The future of leukemia treatment

9/11/2004
By: Ivanhoe Broadcast News

Researchers say about 500 children are diagnosed with acute myeloid leukemia each year. Acute promyelocytic leukemia (APL) is a subtype of the cancer acute myeloid leukemia (AML). It accounts for about 1 percent of all childhood leukemia cases. The disease is characterized by an abnormal form of white blood cells. These abnormal blood cells in the bone marrow and peripheral blood replace normal blood cells.

APL is most often found in children between ages 2 years and 3 years, and in adults over age 40. However, it has also been found in older children and teenagers. APL is more common among children of Hispanic and Mediterranean origin.

Early diagnosis of APL is important because patients may develop serious blood-clotting or bleeding problems. This can usually be prevented or treated by giving patients blood thinner medications. Other treatments might include transfusions of platelets or other blood products. With modern therapies, bleeding is often less of a problem once treatment of APL begins.

Standard treatment for APL patients includes chemotherapy along with an oral form of vitamin A known as ATRA. With this treatment, about 75 percent to 80 percent of APL patients are expected to survive. Side effects of the combined treatment include breathing problems due to lung fluid buildup, low blood pressure, kidney damage and severe fluid retention.

Researchers from the M.D. Anderson Cancer Center in Houston are studying a new, chemotherapy-free alternative for patients with APL. The treatment uses a form of ATRA, known as lipoATRA. LipoATRA is simply ATRA wrapped in fat and injected. Researchers tested the therapy on 34 patients. It won't work for everyone, but results show lipoATRA kept 10 of the 34 patients in remission for several years without having to undergo chemotherapy. The remaining patients who did not respond as well to the lipoATRA treatment had to undergo chemotherapy. There are still side effects with lipoATRA and they may not be any better than side effects seen with chemotherapy.

The treatment is not yet approved by the FDA, and researchers say it does not offer any practical benefits at this time for patients with APL. However, they say their study is significant because it demonstrates how the future of leukemia will be treated.

"It's, I think, probably the first demonstration in the field of leukemia that you can cure patients without giving them chemotherapy. It's plausible to defer chemotherapy and still wind up okay," Elihu Estey, M.D., said.

For more information, contact

Elihu Estey, M.D
The University of Texas
M.D. Anderson Cancer Center
1515 Holcombe Blvd.
Unit 428
Houston, TX 77030-4009

Oranges, bananas and turmeric prevent leukemia

September 16, 2004

ISLAMABAD, September 17 (Online): Giving infants oranges and bananas regularly may halve their risk of developing childhood leukemia, suggest the results of a new study.

And a diet containing the curry spice turmeric may also be protective - accounting for the differences in childhood leukemia rates between east and west - says a leading scientist.

Children who ate oranges, orange juice or bananas between four to six times a week during their first two years of life had a significantly reduced risk of developing the cancer, revealed the observational study by US researchers.

Previous studies on childhood leukaemias have not examined the effects of the overall diet in this way, focusing more on possible risk foods like cured meats.

"Our study is unique, and we have elucidated a significant protective association with the consumption of oranges, bananas and orange juice," says Marilyn Kwan, an epidemiologist at the University of California, Berkeley.

However, she cautions that without carrying out a randomised controlled trial, it is difficult to predict exactly how protective eating these fruits may be, or to make firm public health recommendations. But she notes that in her study "there was a 50 per cent reduction in risk".

The evidence for oranges and bananas, and turmeric in preventing leukaemia was presented at Children with Leukaemia's international leukaemia conference in London, UK, on Thursday.

Oranges and bananas may protect against childhood leukemia because they are a rich source of vitamin C, which is an antioxidant. They could act by reducing oxidative DNA damage, and so stop the initiation of cancerous processes.

Bananas are also rich in potassium. Animal studies have indicated that potassium stabilises DNA and can reduce rates of mutation

Afraid that cancer will return, doctors treat "cure'' like a four-letter word

MARILYNN MARCHIONE, AP Medical Writer
September 18, 2004

There wasn't any doubt six years ago that Doug Jensen had cancer. The Oregon engineer's blood was clogged with the immature cells that are sure signs of leukemia. Treatment with a new wonder drug, Gleevec, made them disappear.

Since then, doctors repeatedly have searched his blood, even individual molecules, for bits of DNA and other substances that would reveal he still had the disease. None has been found. Is he cured? "They don't use that word," said Jensen, who would dearly love to hear it.

Ironically, at a time when more people are cured of cancer than ever before, fewer doctors seem willing to say so. They call the cancer undetectable, or in remission. They tell patients they can quit seeing cancer specialists. They quote statistics and say chances are slim that the disease will come back.

They say these things because the simple truth is, they can't tell when or if someone has been cured. Even the most widely used benchmark -- being alive five years after diagnosis -- has no real basis in science, experts admit.

There's a label for people like Jensen who are in cancer limbo -- "survivor."

Some wear it with pride, having fought the enemy and lived to tell about it. Others think it drafts them into a club to which they don't want to belong -- Veterans of Forever Wars.

Nearly 10 million Americans have battled cancer, including 1.4 million who had it more than 20 years ago and are called "long-term survivors" by those afraid to call them cured.

Their ranks include Lance Armstrong, who heads a survivorship foundation and boasts of beating testicular cancer that had spread to his lungs and brain. Can he ever be declared cured, or must he always carry "survivor" with his Tour de France titles?

"The medical community has backed off the term 'cured,"' said Julia Rowland, a psychologist who directs the federal Office of Cancer Survivorship, which was started in 1996, the year Armstrong began treatment.

The reasons involve more than just semantics, she and others say. Cure is a term with emotional and medical meanings about which there is little agreement.

To many people, it means that the cancer is gone and is not going to come back.

But some cancers -- certain lymphomas and leukemias in particular -- never go away completely yet are controlled so that they're no longer life-threatening. Some call that a remission, but others consider it a cure.

Other cancers look like they've gone away -- no signs of them can be found by exquisitely sensitive and sophisticated tests -- but recur many years later, suggesting that they weren't really cured after all. Breast cancer is notorious for this.

"What today does 'cure' really mean?" asked Dr. Len Lichtenfeld, deputy chief medical officer of the American Cancer Society. "Does that mean there's no cancer cells in your body from this cancer any more, or does that mean that at this particular time, there's only 2, 3, 4 5 percent chances it's going to come back?"

He's not the only one trying to define the concept.

"It's something we've had discussions about internally," said Diane Balma, public policy director for the Susan G. Komen Breast Cancer Foundation, which calls its fund-raiser Race for the Cure, not Race for the Remission.

She is distrustful of absolutes. Diagnosed with breast cancer at age 30 but with no sign of it nearly a decade later, "I will never consider myself cured," she said. "Cure means there's no possibility of recurrence, and that's why I don't like the word. We all know there's a possibility of recurrence."

Ellen Stovall, who had Hodgkin's disease and now heads an advocacy group, the National Coalition for Cancer Survivorship, tries to ignore the issue.

"Cure is a term that I don't need to have in order to fell well and healthy," she said. "It's a word without meaning in some respects. It may be useful for testifying before Congress or getting a job," but it doesn't predict future health.

When doctors do declare someone cured, how can they tell?

In the past, it was when they could cut out a tumor and surrounding tissue until no more abnormal cells could be seen. Many doctors today are willing to call testicular, prostate and certain other kinds of cancer cured if the tumors are small and confined to a gland or organ that can be removed.

But Dr. David Carbone, a lung cancer expert at the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., would be reluctant to say that about the type of cancer he treats.

"All the time, I see patients who had surgery done and the surgeon says they got it all, they're cured. Statistically, they may have a good chance of being cured. But it's all a probability. Has that surgeon done them a favor by saying that?"

The opposite situation also is true: Doctors sometimes declare a cancer cured even after it had spread beyond the place it originated. This used to be considered an inevitably terminal condition, but it's often conquered now with chemotherapy, radiation and other treatments.

Still, it's much harder to predict someone's ultimate survival after cancer has spread. Doctors look at factors like how aggressive a tumor is and where and how quickly it traveled, but not all patients get such tests. Most of the time, only time will tell.

"Some of these people have long-term survival, and some of them are going to be cured of their disease. We don't know what to tell them," Lichtenfeld said.

Which is why many doctors turn to statistics, and five-year survival is their favorite. By that measure, cancer surely is being cured: Nearly two out of three patients make it to that point today; only half did 25 years ago.

However, there is nothing magical about that benchmark. Survival is a continuum, and five years is no more meaningful a dividing point than two, three, six or nine years.

"I honestly don't know where that came from. It goes back a long time," said Rowland at the federal cancer agency. She and others think it grew from a need to have some way of measuring survival and tracking cancer trends in the overall population.

More relevant statistics take into account the type of cancer someone has. With some, like bladder cancer and many of the blood and bone marrow malignancies, if someone is alive after a year or two, their long-term outlook is pretty good. But much to the chagrin of breast cancer advocacy groups and people with the deadly skin cancer melanoma, five-year survival doesn't bring great assurance that those diseases won't come back years later.

Dr. David Johnson, deputy director of Vanderbilt-Ingram Cancer Center and president of the American Society of Clinical Oncology, thinks the five-year benchmark became balm for doctors and patients who found the unpredictability of their situations intolerable.

"Physicians were reluctant to say 'you might recur,' so they'd use these terms like 'OK, in five years, you'll be cured,"' he said.

Johnson and his colleague, Carbone, both have survived lymphoma and are past the five-year mark. But statistics only tell what happens to the masses, not to individual patients.

"They can't be half-cured, like they can't be half-pregnant. So a lot of time discussing percentages often isn't productive," Johnson said.

"You're either cured or you're not," Carbone agreed.

Complicating matters is the risk of second cancers. Some of the very treatments used to cure cancer, like chemotherapy and radiation, actually can trigger new cancers down the road. People with an inherited genetic flaw that predisposed them to cancer still have that underlying problem after being treated successfully.

"The fact that you've had cancer once means that you can get it again," Johnson said.

But some of the trickiest situations today involve people like Jensen. Average survival for his form of cancer, chronic myelogenous leukemia, was only five years until 2001, when Gleevec, one of a new generation of drugs that more precisely target cancer, came on the market.

More than 95 percent of CML patients do stunningly well on Gleevec, "but this may be more akin to controlling diabetes with insulin than curing diabetes," said Dr. Brian Druker, the Oregon Health & Science University cancer specialist who pioneered the drug's development.

"When we look at our patients with extremely sensitive techniques, we can still see leukemia cells," he said. "Our concern is that if we stop Gleevec, then their leukemia will come back. Are they cured? Probably not. Are they well controlled? Absolutely, yes."

Jensen is one of the few CML patients who show absolutely no sign of cancer. He has taken Gleevec since 1999, when he enrolled in an experiment that still provides him the drug for free. It doesn't make him sick because it attacks the root causes of his cancer without killing healthy cells.

He feels like he could take it forever, and wants to. But he and his doctors are considering taking him off.

"I honestly don't know what the right thing to do is," but stopping the drug is the only way to find out if he and others like him are cured, Druker said.

"That's a little scary, I have to admit. Everything's going along so well," Jensen said. But he talked it over with his wife and decided that if Druker and his other doctors ask him to, he'd probably go off the drug.

"They say it's undetectable," he said of his cancer. "I'd like to have them say I'm cured."

Cancer Dies When 'Defect' Fixed

Sept. 20, 2004

"Abnormalities in genes affecting [programmed cell death] have been found in nearly every cancer, suggesting they may be necessary to develop cancer."
Researcher Anthony Letai

(WebMD) Fixing a defect in cancer cells makes them die a natural death, a study in mice shows. The finding means that a series of new anticancer drugs already in development are likely to work. They may work very well indeed, the study suggests.

When normal cells reach the end of their useful life, they self-destruct. This suicide process is called programmed cell death or apoptosis. But cancer cells have a defective self-destruct program. They make too much of a molecule called BCL-2, which gobbles up the chemical messengers that activate cell suicide.

Anthony Letai, MD, PhD, Stanley Korsmeyer, MD, and colleagues at Dana-Farber Cancer Institute wondered what would happen if they stripped cancer cells of their BCL-2 armor.

"What better way to kill cancer cells than targeting the molecules that directly control their survival?" Letai asks in a news release.

To see what would happen if cancer cells didn't have BCL-2 protection, the researchers created a strain of genetically engineered mice whose BCL-2 could be switched off by a common antibiotic. The mice also carried a gene that gave them leukemia.

By the age of 7 weeks, all 28 test animals had leukemia. All 14 mice that continued making BCL-2 died of leukemia by 100 days of age. But the 14 treated animals, who received the antibiotic in drinking water, had their BCL-2 cut off. All of them had fewer leukemia cells, and their white blood cells numbers became normal within days of therapy. Five of these mice lived for more than 200 days, and one lived for more than a year.

That's exciting news. Until this experiment, nobody was sure that simply removing the barrier to cell suicide would result in cancer-cell death.

"Abnormalities in genes affecting [programmed cell death] have been found in nearly every cancer, suggesting they may be necessary to develop cancer," Letai and colleagues write in the September 2004 issue of Cancer Cell.

Several drug companies are working on treatments that would block BCL-2. BCL-2 is crucial for proper immune function. But the mouse studies suggest that humans could tolerate a temporary BCL-2 block long enough for such future drugs to have an anticancer effect.

Senior study author Korsmeyer serves on the scientific advisory board of IDUN Pharmaceuticals, which is developing cell-death therapeutics.

SOURCES: Letai, A. Cancer Cell, September 2004; vol 6: pp 241-245. News release, Dana-Farber Cancer Institute, Boston.

By Daniel J. DeNoon
Reviewed by Brunilda Nazario, MD

ZIOPHARM Presents Data on New Class of Arsenic Compounds at International Leukemia Meeting

NEW HAVEN, Conn., Sept. 20 /PRNewswire/ -- ZIOPHARM today announced that Dr. Srdan Verstovsek, MD, and his colleagues at The University of Texas M. D. Anderson Cancer Center reported mouse study data on the company's lead compound, ZIO-101, showing they were able to increase the arsenic dose 30- to-50-fold over that of inorganic arsenic without experiencing any severe side effects. Further testing with ZIO-101 in dogs showed no evidence of heart damage or other severe toxicity.

The findings were presented at the seventh annual meeting of New Trends in the Treatment of Acute Leukemia, September 11-14 in Dubrovnic. The conference addressed recent developments and progress in treating the disease and included both US and European experts. One of the highlights of the meeting was the presentation on ZIO-101, the first in a class of new organic arsenicals.

Currently, inorganic arsenic therapy has been shown to be highly effective in treating a rare form of leukemia called acute promyelocytic leukemia (APL). However, physicians have been impeded in using inorganic arsenic at higher doses to treat other blood cancers and much more common solid cancers because of the risk of damage to the heart and other serious toxicities from increasing the dose of inorganic arsenic.

The M. D. Anderson team also presented laboratory data that suggests ZIO-101 kills cancer cells more effectively than inorganic arsenic by using different mechanisms. The Company has targeted a late 1Q 2005 starting date for phase I study in hematological cancer and a second study shortly thereafter for solid tumors.

About ZIOPHARM
ZIOPHARM, Inc. is a privately held company. It was founded in January 2004 to develop and commercialize a diverse, risk-sensitive portfolio of in-licensed cancer therapies. All products are focused on addressing unmet medical needs, with the potential for expedited approval and broad usage.

ZIOPHARM's first in-licensed product, ZIO-101, is a small molecule from The University of Texas M. D. Anderson Cancer Center and is planned for Phase I study initiating late in 1Q-2005. The company anticipates licensing of ZIO-201 by 4Q-2004.

ZIOPHARM is actively evaluating and negotiating for additional product candidates with the objective of a balanced portfolio of at least three clinical-stage compounds and at least one late preclinical candidate by the end of 2005. Each product candidate undergoes a tightly managed evaluation process leveraging the company's management team's combined 100+ years of oncology experience in clinical development, regulatory strategy, business development and product commercialization.

Both ZIOPHARM's structure and mission set it apart from other cancer drug companies. The company's rigorously disciplined approach to screening product candidates is designed to accelerate clinical programs while reducing the expense and risk typically incurred in researching, developing and launching new cancer products. With an intimate understanding of the regulatory approval process, the company expects to break new ground as regards to speed and efficiency as it brings new cancer compounds to market.

CONTACT: ZIOPHARM, Inc., IR/Media Relations, +1-203-848-3414

Maxim swoons after cancer drug flunks key trial

Company will continue to explore uses for Ceplene
By Terri Somers
UNION-TRIBUNE STAFF WRITER
September 21, 2004

Maxim Pharmaceuticals shares dived almost 50 percent yesterday after the San Diego biotechnology company said its drug Ceplene failed to increase survival rates in a critical trial with advanced skin cancer patients.

The company had aimed to win U.S. and European approvals to market the drug for patients with malignant melanoma that has metastasized to the liver. Maxim already had received U.S. approval to provide Ceplene as an experimental treatment to critically ill melanoma patients, even though the drug was still being tested.

But the trial results make it unlikely the drug will receive the final approvals the company had hoped for, Maxim chief executive Larry Stambaugh said.

Maxim shares were down $2.90, or 49 percent to $3.04 at the close of Nasdaq Stock Market yesterday, a new one-year low.

The trial was a "must-do" for the company to get approval for Ceplene, and the failure represents a "major setback," Merriman Curhan Ford & Co. analyst Kate Winkler wrote in a report. Winkler lowered her rating on the company's shares to "sell" from "buy."

But despite the setback, Stambaugh said the 12 years and millions of dollars the company has spent developing the drug are not lost.

In May the company reported that when used on patients with leukemia, a combination of Ceplene and interleukin-2, a common cancer treatment, produced a statistically significant improvement in leukemia-free survival.

"We had intended to file for regulatory approval (to treat) leukemia second, after we received melanoma approval," Stambaugh said. "Treatment of leukemia will now move up to first."

The company is also testing the drug in treating kidney, intestinal and colorectal cancers.

The latest Phase 3 trial on patients with malignant melanoma, the most deadly form of skin cancer, was not the first with disappointing results.

In 2000, the FDA rejected Ceplene for treating melanoma based on another Phase 3 trial. The company went back to work on the drug and hoped this trial would produce better results.

The company submitted an application in November seeking European marketing approval for the use of Ceplene as a treatment for malignant melanoma. It had hoped to win that approval by the end of the year.

The company does not plan to immediately scrap all its plans for the drug's use on melanoma, Stambaugh said.

"It's too early to make that decision," he said. "We haven't reviewed all the data."

"We are perplexed," he said. "After several trials it showed promise in this very tough cancer. We'll have to see if it is still possible we could learn something that will allow us to work with melanoma, which has become the fastest growing cancer without any effective treatment."

In addition to Winkler, other analysts also lowered their ratings on Maxim's stock. Rodman & Renshaw lowered Maxim's shares from market perform to market underperform. Earlier in the year the company had rated Maxim market outperform.

Handelsbanken Capital Markets downgraded Maxim from a buy to a sell.

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