Platinum and Blue Light Combine to Combat Cancer

Research led by the University of Warwick, along with researchers from Ninewells Hospital Dundee, and the University of Edinburgh, have found a new light-activated platinum-based compound that is up to 80 times more powerful than other platinum-based anti-cancer drugs and which can use "light activation" to kill cancer cells in a much more targeted way than similar treatments.

The University of Warwick team had already found a platinum-based compound that they could activate with ultra-violet light but that narrow wave length of light would have limited its use. Their latest breakthrough has discovered a new platinum based compound known as trans,trans,trans-[Pt(N3)2(OH)2(py)2] that can be activated by normal visible blue, or even green, light. It is also stable and easy to work with, and it is water soluble so it can simply dissolve and be flushed out of the body after use.

The University of Warwick researchers passed the new compound to colleagues at Ninewells Hospital Dundee, who tested it on esophageal cancer cells cultivated within lab equipment. Those tests show that once activated by blue light the compound was highly effective requiring a concentration of just 8.4 micro moles per litre to kill 50% of the cancer cells. The researchers are also beginning to examine the compound’s effectiveness against ovarian and liver cancer cells. Early results there are also excellent but that testing work is not yet complete.

Professor Peter Sadler, from the Department of Chemistry from University of Warwick, who led the research project, said: "This compound could have a significant impact on the effectiveness of future cancer treatments. Light activation provides this compound’s massive toxic power and also allows treatment to be targeted much more accurately against cancer cells."

"The special thing about our complex is that it is not only activated by ultra-violet light, but also by low doses of blue or green light. Light activation generates a powerful cytotoxic compound that has proven to be significantly more effective than treatments such as cisplatin."

We believe that photoactivated platinum complexes will make it possible to treat cancers that have previously not reacted to chemotherapy with platinum complexes," says Sadler. "Tumors that have developed resistance to conventional platinum drugs could respond to these complexes and with less side-effects."

This research has been supported by the EPSRC, MRC, ERC and Science City (ERDF/AWM).

Fatherhood Possible For Many Testicular Cancer Survivors, Study Finds

Testicular cancer, the most common cancer among men ages 20 to 40, has a high cure rate: 95% of patients are cured through treatment. Because many of these patients are diagnosed at an age when they are starting a family, the ability to father children after treatment is often a concern. However, there are little reliable data on post-treatment fertility available to guide these men.

To assess post-treatment fertility among testicular cancer survivors, Marianne Brydøy, M.D., of Haukeland University Hospital in Bergen, Norway, and colleagues studied 1,814 men who had been treated for testicular cancer in Norway between 1980 and 1994 who had been invited to participate in a follow-up survey between 1998 and 2002.

Of the 1,433 men who were assessable, post-treatment conception was attempted by 554, and 71% were successful within 15 years of treatment (without the use of cryopreserved semen) and 76% were successful within 20 years. Success varied by type of treatment, ranging from just 48% among men treated with higher doses of chemotherapy to 92% among men followed by surveillance alone (after removal of the testicle affected by cancer). The median time from diagnosis to birth of the first child was 6.6 years, but this also varied with treatment type. About 22% of couples who attempted post-treatment conception reported that they needed some form of assistance with reproduction.

"With recent advances in assisted fertility techniques, more testicular cancer survivors may be helped to father children. However, because infertility cannot be predicted on an individual basis, it is important to continue the policy of offering sperm preservation prior to treatment," the authors write.

In an editorial, Scott Saxman, M.D., of the National Cancer Institute, notes that the results of this study will help physicians to provide answers to testicular cancer patients who are concerned about their ability to father children, although some of the data may no longer be relevant because of improvements in treatments now available. "Clearly the impact of therapy on fertility, as well as other long-term complications, for men with testicular cancer needs to be better categorized and understood," he writes. "However, this will be a moving target as treatment approaches continue to change and improve. Seriously addressing these public health issues for patients in the United States will require a national collaborative effort that identifies and collects, on an ongoing basis, longitudinal information on the health status of these men."


Note: The Journal of the National Cancer Institute is published by Oxford University Press and is not affiliated with the National Cancer Institute. Attribution to the Journal of the National Cancer Institute is requested in all news coverage. Visit the Journal online at jncicancerspectrum.oxfordjournals/.

Study Offers Innovative Profile Of Enzyme That Aids Tumor Growth

"Using a combination of enzyme activity and metabolite profiling, we determined that this protein-whose function was previously unknown-serves as a key regulator of a lipid signaling network that contributes to cancer," said Benjamin F. Cravatt, a Scripps Research professor and a member of its Skaggs Institute for Chemical Biology who led the study. "The heightened expression of KIAA1363 in several cancers indicates that it may be a critical factor in tumorgenesis. In addition, network components, including KIAA1363 itself, might be considered potential diagnostic markers for ovarian cancer."

This experimental method of integrated molecular profiling used in the study should also advance the functional study of metabolic enzymes in any biological system, according to Cravatt.

To date, understanding the roles of uncharacterized enzymes in cell physiology and pathology has remained problematic. Typically, the activities of enzymes have been studied in vitro using purified protein preparations. The outcome of these test-tube studies can be difficult to translate into clear characterizations of the roles that enzymes play in living systems, where these proteins generally operate within larger metabolic networks.

A primary advantage of metabolite profiling in natural biological systems is that it circumvents some of the most time-consuming steps that accompany in vitro enzyme analysis while generating data more directly related to their naturally occurring activities.

"Our hypothesis was that the determination of catalytic activities for enzymes like KIAA1363 could be done directly in living systems through the integrated application of profiling technologies that survey both the enzymatic proteome and its primary biochemical output, the metabolome," Cravatt said.

So, the team drew both on proteomics-the large-scale study of the structure and function of proteins-and metabolomics-the systematic study of cellular processes, specifically their small-molecule metabolite profiles-to begin to decipher the complex metabolic and signaling networks of cancer.

According to the study, one of the primary advantages of the functional proteomic technology employed (activity-based protein profiling) is that it can be used to identify inhibitors for uncharacterized enzymes like KIAA1363. Moreover, because inhibitors are screened against many enzymes in parallel, both potency and selectivity factors are assigned simultaneously.

The development of a selective inhibitor of KIAA1363 was possible due to the availability of an activity-based proteomics probe for this enzyme. Such probes are now available for many enzyme classes that participate in cell metabolism, so Cravatt suggests "a large swath of the enzyme proteome" could be addressed using the study’s experimental strategy.

"The success of our study opens the door to assembling the full range of enzymes into both metabolic and signaling networks contributing to complex pathologies like cancer," Cravatt said. "This could lead to the discovery of new markers for diagnosis and targets for treatment."

The study is the cover story of the October 23 issue of the journal Chemistry & Biology.

Other authors of the study, "An Enzyme that Regulates Ether Lipid Signaling Pathways in Cancer Annotated by Multidimensional Profiling," include Kyle P. Chiang, Sherry Niessen, and Alan Saghatelian of The Scripps Research Institute.

This work was supported by the National Institutes of Health, the California Breast Cancer Research Foundation, the ARCS Foundation, the Life Sciences Research Foundation, the Burroughs Wellcome Fund, and the Skaggs Institute for Chemical Biology at Scripps Research.

Drowsy Fruit Flies Illuminate First Molecular Pathway, In Any Species, Known To Regulate Rest And Wakefulness

The findings, from a team led by Joan C. Hendricks of Penn’s Center for Sleep and Respiratory Neurobiology, are reported in the November issue of the journal Nature Neuroscience. The work indicates that a Drosophila melanogaster gene known as CREB – evolutionarily conserved in species from flies to humans – plays a role in rest’s rejuvenating effects, apparently permitting sustained wakefulness.

Anyone who’s ever pulled an all-nighter knows by the next morning that sleep is essential, and sleep’s status as a behavior found in organisms ranging from fruit flies to frogs to humans underscores its importance as a biological process. But 50 years after the discovery of REM sleep, scientists still know little, on a molecular level, about why sleep is needed and the exact benefits conferred by a daily period of rest.

The Penn researchers say that in addition to offering answers to such fundamental questions, the new work could help improve the efficacy and safety of the ways people alter their sleep patterns.

“If we can get at basic mechanisms of how sleep is normally controlled, and what it does for us, we can start to think of how to control, manage and improve sleep,” said Hendricks, a professor in the Philadelphia Department of Clinical Studies at Penn’s School of Veterinary Medicine. “This would be helpful for people subjected to changes in sleep schedules and for people with sleep disorders.”

Hendricks’ group first described Drosophila sleep in a paper published last year in the journal Neuron. Rest in flies shares numerous similarities with human sleep, including prolonged immobility, decreased sensory responsiveness and a need to compensate after sleep deprivation. Fruit flies spend about six to 10 hours a day resting, mostly at night.

“The sleeping flies lie prone in a quiet corner, unresponsive to stimuli, for bouts averaging about 45 minutes but sometimes lasting up to two-and-a-half hours,” Hendricks said. “These sessions are interspersed with very brief, one- to two-minute interruptions, during which they eat and groom and then settle back down.”

The Penn researchers’ new findings indicate that the activity of CREB, short for cyclic AMP response element binding protein, is inversely related to the physiological urge for rest. The need for sleep after a phase of deprivation – attained through the mechanical agitation of fly habitats roughly every 15 seconds for as long as six hours – surged in flies whose CREB activity was blocked. In normal flies, CREB activity remains elevated for some 72 hours after such a prolonged period of wakefulness; CREB mutants slumber even longer than normal flies in the aftermath of deprivation.

CREB, which is evolutionarily conserved in species from slugs to mice to humans and already known to function in cyclic AMP signaling, is also known to play an important role in learning in fruit flies. Hendricks’ work could strengthen the link that many researchers believe exists between rest and the consolidation of memory.

The Penn group is continuing its studies of how CREB is turned on, as well as the target genes affected by its activity. They suspect that CREB activation during rest may somehow optimize the function of the central nervous system during waking hours.

Hendricks’ co-authors on the Nature Neuroscience paper are Julie A. Williams, Karen Panckeri, David Kirk and Amita Sehgal, all of Penn, and Marcela Tello and Jerry C.-P. Yin of the Cold Spring Harbor Laboratory in New York. Their work is funded by the National Institute of Heart, Lung and Blood and the Howard Hughes Medical Institute.

Incontinence Treatment: Muscle-Derived Stem Cells Prove Effective In Reparing Sphincter Damage To Restore Continence

Certain medical procedures, including transurethral resection of the prostate and radical prostatectomy can result in damage to the external urinary sphincter. In one study, a German research team successfully implanted muscle cells grown from tissue from the patients’ deltoid muscles into the damaged sphincter.

One year later, four patients were completely continent and 19 patients had improved from grade III to grade I incontinence. With more than half of the patients experiencing an improvement in continence after four months, the use of muscle-derived cells to repair sphincter damage proved successful. Minor side effects were observed in five patients.

A second study reaffirmed these findings. Using muscle cells from the upper arms of 65 incontinent men who had undergone a prostatectomy, researchers in Austria grew the cells in a laboratory and then implanted them. Patients were evaluated before the surgery to define their level of incontinence and evaluated post-operatively to monitor complications.

Prior to therapy, the mean number of pads used per day was 4.89, and after treatment, the mean number of pads decreased to 1.59. 27.9 percent of patients did not wear pads at all and 43.6 percent reported that they only required a pad for “special occasions.” Only 28.5 percent of patients still required pads.

New Mutant Mouse Repositories Established For Biomedical Research Community

“When numerous researchers have access to a shared national resource, such as the MMRRC network,” says NCRR Director Dr. Judith Vaitukaitis, “the effectiveness of that resource is maximized relative to its monetary cost and scientific impact.” She adds, “Shared resources allow scientists to integrate diverse research expertise, rapidly and effectively study emerging health problems, address complex research queries, and pursue unexpected research opportunities.”

The MMRRC network currently includes four repository-distribution facilities located at the University of North Carolina at Chapel Hill; the University of California at Davis; Taconic Farms in New York; and Harlan Sprague Dawley, Inc., in collaboration with the University of Missouri.

The MMRRC network is electronically linked through an NCRR-sponsored MMRRC Informatics Coordinating Center (ICC) to function as one facility. The ICC, which is located at The Jackson Laboratory in Bar Harbor, Maine, provides database and other informatics support to the MMRRCs to give the research community a single entry point to the network through the MMRRC Web site at www.mmrrc. This site provides information about submitting candidate strains. By late 2001, the site will also provide detailed phenotypic and genotypic information to researchers interested in searching the network for maintained strains, ordering mice from the facilities, and registering to receive strains being developed.

Generally, each MMRRC facility is equipped to cryopreserve embryos or gametes; rederive strains as needed; and characterize the genetic and phenotypic makeup of the mutants so that models are validated and may optimally serve as models of human disease. Efficient facility systems provide genetic quality control and disease safeguards. The MMRRCs offer expertise in the biology of laboratory mice — covering areas of cryobiology, genetics, comparative pathology, behavioral science, and infectious disease. In addition, each center focuses on specific research areas such as vascular and cancer biology, endocrinology, or neurobiological sciences.

NCRR is this nation’s leading Federal sponsor of research resources that enable scientific advances and discoveries in many areas of biomedical research. NCRR-supported research resources provide the scientific research community with access to a diverse array of research technologies, instrumentation, specialized basic and clinical research facilities, animal models (mammalian and nonmammalian), genetic stocks, and biomaterials, including cell lines, tissues, and organs.

Personalized Therapy For Asthma And COPD Could Soon Be Here

"We’ve cracked the first part of the molecular code that links a viral infection to the later development of chronic inflammatory diseases like asthma and COPD," says senior author Michael Holtzman, M.D., the Selma and Herman Seldin Professor of Medicine, director of the Division of Pulmonary and Critical Care Medicine and a pulmonary specialist at Barnes-Jewish Hospital. "With this information, we can more precisely diagnose and monitor these types of diseases and then better target our treatment to specific abnormalities. That’s a big step forward from simply monitoring breathing status."

The findings, published in Nature Medicine, promise a way to determine whether a patient’s asthma or COPD is the result of a chronic immune response that can be turned on by a respiratory viral infection. Guided by these new findings, this type of immune response could be detected by monitoring specific types of inflammatory cells or molecules in the lung or potentially in the bloodstream, giving physicians a more precise approach to diagnosis and treatment of lung disease.

This type of testing could eventually tell physicians whether a patient’s condition is mild, moderate or severe, as well as track the effectiveness of treatment. It could also lead to the development of new types of drugs that target the underlying cause of inflammatory lung disease.

"With our results, we can now work on developing more rational ways to diagnose and monitor lung conditions such as asthma and COPD," Holtzman says. "As it stands now, the diagnosis of chronic lung disease generally depends on clinical judgment and standardized tests of lung function, but we have little that tells us what’s going on in the patient’s lungs at the cellular and molecular level."

Asthma and COPD are both serious lung diseases that cause shortness of breath, wheezing, coughing and fatigue. In the United States, about 20 million people have been diagnosed with asthma and about 12 million with COPD, which includes emphysema and chronic bronchitis. Holtzman’s research aims to find therapies for these disorders that modify the underlying causes of the disease instead of simply suppressing symptoms as most present-day treatments do.

In this study, Holtzman and colleagues found that a common type of viral infection of the lung can leave behind a persistent trace of the virus. This viral remnant likely becomes an ongoing stimulus for a chronic immune response, which could last for long periods, even a lifetime. This response causes the cells in the lung passages to overproduce mucus and become hyper-reactive to irritants.

The research team uncovered the details of this immune process by studying mice that are infected with a respiratory virus that is very close to the type of viruses that cause similar infections in humans. When the mice got over their infection, they were left with chronic airway disease characterized by mucus production and increased airway reactivity to an inhaled irritant.

A key molecular feature of this chronic disease was the production of a powerful natural inflammatory substance, interleukin-13 (IL-13). Investigating the source of IL-13, the researchers tracked down a previously undescribed type of immune pathway. This pathway is part of the immune system that is supposed to be activated for only short periods of time. However, the investigators found that the pathway can also be persistently activated after viral infection, likely due to the pathway’s ability to respond to viral remnants.

Under these conditions, they also found that the pathway is set up to amplify its own activity. This combination of persistent activity and positive feedback leads to the long-term production of IL-13 as well as other substances that then cause continuous inflammation in the lung tissue and the development of chronic lung disease.

The team of investigators confirmed that the same immune process could also be detected in the lungs of people with severe asthma and COPD. This type of immune response is typically associated with parasitic infections and allergic disease, but here it appears to be linked to viral infection and chronic inflammatory disease. Importantly, the response produces a specific array of compounds that can be detected in the lung and likely in the blood to serve as diagnostic markers of disease. The research team is now working to verify that the profile of biomarkers for this immune response can be used to diagnose patients with asthma and COPD.

In another recent article, Holtzman and colleagues identified another new type of immune mechanism that developed after respiratory viral infection and led to inflammatory lung disease. In this case, the virus triggered an allergic-type antibody response to cause the later development of disease. This pathway did not stay active quite as long but it still caused changes in the airways of the lungs that were similar to the disease found in humans with chronic asthma. The new findings show that patients with severe asthma and COPD may also share some mechanisms that cause their disease.

"Now, we have identified two new immune pathways that lead to chronic lung disease, and we already have evidence for additional pathways," Holtzman says. "Our goal is to find distinct biological markers for each pathway. This will tell us how to diagnose and what to treat. Then, we must develop therapeutics that are directed to each type of response so that physicians can deliver a treatment that is tailored to the specific type of asthma or COPD found in that patient."

Deciphering these unique immune pathways also can identify new targets for drugs that could block the harmful immune responses, according to Holtzman. He says the findings could also make drug development much more accurate.

"There appear to be many distinct ways to cause asthma or COPD. If an experimental drug works on only one of these causes, it is likely to fail in drug trials that include a broad range of patients," he explains. "But if we can set up trials so the test drug is targeting a specific immune response and is given only to those who have that type of response, then we can more accurately determine whether the drug is beneficial."

Funding from the National Heart, Lung, and Blood Institute, National Cancer Institute, and National Institute of Allergy and Infectious Diseases, the Barnes-Jewish Hospital Foundation, the Martin Schaeffer Fund and the Alan A. and Edith L. Wolff Charitable Trust supported this research.

Memory Restored In Mice Through Enriched Environment: New Hope For Alzheimer’s

The new studies suggest two promising avenues for treatment that might alleviate learning deficits and memory loss in humans with Alzheimer’s disease or other neurodegenerative diseases.

The results of the experiments suggest that the term "memory loss" may be an inaccurate description of the kinds of mental deficits associated with neurodegenerative diseases. "The memories are still there, but they are rendered inaccessible by neural degeneration," said the senior author Li-Huei Tsai, a Howard Hughes Medical Institute researcher at the Massachusetts Institute of Technology.

"I believe that these findings could have particular significance for treatment of people who already have advanced neurodegenerative disease," said Tsai. "Most current treatments seem to be aimed at affecting the early stages of the disease. But our mouse model shows that even when there has been a significant loss of neurons, it is still possible to improve learning and memory."

Over the last five plus years, Tsai’s research team has developed and refined a mouse model of Alzheimer’s disease. In earlier studies, Tsai’s group had shown that a protein called p25 contributes to neurodegeneration. Over time they developed a genetically engineered mouse in which they are able to turn on p25 gene expression at specific stages in development. In these animals, evidence of neuronal loss is first detected six weeks after the induction of p25. At this age, animals exhibit a profound impairment in learning and memory that is accompanied by synaptic loss and impaired long-term potentiation (LTP), a process involved in the storage of memories.

The researchers engineered mice so that they could switch the p25 transgene on at will. Activation of p25 has been implicated in a variety of neurodegenerative diseases. Once activated in the mice, the p25 transgene produces neural pathology very similar to that of patients with Alzheimer’s disease, said Tsai. The animals show brain atrophy and loss of neurons due to the same kind of cellular abnormalities seen in people who have Alzheimer’s disease, she said.

Researchers have long known that an environment rich in sensory stimuli can improve learning in mice. So, Tsai and her colleagues decided to explore whether such an environment could improve learning and memory in their mice after a large number of neurons were already lost.

In their experiments, they switched on p25 in older mice. The genetic change induced brain atrophy and neuronal loss. They then used two tests to assess learning and memory in these older mice. In the "fear-conditioning" test, the animals were required to learn to associate a specific chamber with a mild electric shock. The second test required the animals to learn to find a submerged platform in a tank of murky water.

The researchers placed some of the animals in a large chamber with a variety of stimuli: an exercise treadmill, colorful toys with various shapes and textures that were changed daily, and other mice. Their experiments showed that animals with neurodegeneration due to p25 activation had significant gains in learning and memory when they were exposed to this enriched environment. Those animals fared better on memory tests than the animals that remained in standard cages.

The researchers also tested the effects of an enriched environment on the animals’ long-term memory. They knew that the fear-conditioning test established a lasting long-term memory in the mice. So, they tested whether environmental enrichment improved the p25-induced animals’ ability to remember that conditioning weeks after training. They found that the enriched animals showed marked recovery of the long-term memory when compared to mice that did not live in a stimuli-rich environment.

"This recovery of long-term memory was really the most remarkable finding," said Tsai. "It suggests that memories are not really erased in such disorders as Alzheimer’s, but that they are rendered inaccessible and can be recovered."

When the researchers studied the brains of the animals that had been exposed to the extra stimuli, they found no evidence of increased growth or formation of new neurons when compared to brains of mice that had not experienced the enriched environment. However, they did find anatomical and biochemical evidence for growth of connections among neurons.

Tsai and her colleagues also sought to understand the biological mechanism by which environmental enrichment enhanced learning and memory in the mice. "Even though the learning-enhancement effects of environmental enrichment have been known for half a century, nobody really knows the mechanism behind it," said Tsai. "However, there has also been a growing body of evidence that chromatin remodeling has a beneficial effect on learning and memory," she said.

Chromatin is found in the nuclei of cells. It is composed of DNA spooled around bundles of histone proteins. The addition of small chemical tags to known as acetyl of methyl groups to the histones can alter the way chromatin is organized, which in turn determines which genes are turned on. Indeed, when Tsai and her colleagues analyzed the histones of enriched mice versus non-enriched animals, they found that environmental enrichment induced histone modification in the enriched mice.

Tsai and her colleagues tested whether a class of drugs that preserves histone acetylation, called histone deacetylases inhibitors, could affect learning and memory in the p25-induced mice. "In those studies, we found that using drugs to increase histone acetylation artificially produced an effect very similar to that observed in environmental enrichment," said Tsai. "This leads us to believe that further studies of ways to target chromatin remodeling could offer a treatment for Alzheimer’s and other forms of dementia," she said. Tsai’s group is now investigating the molecular mechanism by which such drugs work and which specific drug targets might be most effective at enhancing learning and memory.

 Tsai led the research group that published its findings on April 29, 2007, in an advance online publication in the journal Nature.

Quitting Smoking: Genetic Research Shows Promise For Personalized Treatment

The study, published in the September issue of the journal Biological Psychiatry, found that the enzyme known to metabolize both the smoking cessation drug bupropion and nicotine is highly genetically variable in all ethnicities and influences smoking cessation.

This finding is a step toward being able to tailor smoking cessation treatment to individuals based on their unique genetic make-up.

"This first study identifies a very common genetic variant (present in anywhere from 25 to 50 percent of world populations) that appears to affect the outcome of smoking cessation treatment," said Rachel Tyndale, Section Head of Pharmacogenetics at CAMH and lead researcher on the study, adding that the results would have to be replicated.

Tyndale and colleagues performed genotyping on smokers for CYP2B6, a gene known to be highly variable and whose enzyme metabolizes bupropion, nicotine and serotonin. Participants were then provided with either placebo or bupropion treatment for ten weeks and followed up for 6 months.

The research project, supported by the Canadian Institutes of Health Research and the National Institute of Health, found that 45% of individuals with a specific variant of the gene benefited from bupropion treatment and maintained abstinence longer while doing poorly on placebo, with a 32.5% abstinent rate vs. 14.3%, respectively.

In contrast, the 55% with a different variant of the gene (wild type variant) had good abstinences rates on placebo and gained no additional benefit from Bupropion, suggesting no benefit from treating these individuals with Bupropion. Of note, this group was able to quit smoking very well in the absence of an active drug (on placebo).

What percentage of people fall into the group that appeared to benefit? Previous studies have shown that 45%, 50% and 25% of White, African and Asian North Americans have the former specific variant form of the CYP2B6 gene.

The current study looked only at people of European ancestry, says Dr. Tyndale, but she and her colleagues have begun a similar study in African American smokers. They hypothesize that the variant form of the CYP2B6 gene will influence the effectiveness of bupropion treatment and ability to quit smoking in the same way in African Americans as in those of European descent.

Blood Screen May Help Cancer Patients Thwart Radiation Side Effects, Say Stanford Researchers

“We’ve been treating cancer patients as if one treatment fits all,” said Gilbert Chu, MD, PhD, professor of medicine and of biochemistry who led the study. “Cancer patients need to be treated for their particular cancer and their own bodies.”

Some factors are a tip-off that a patient may have an unusually severe reaction to radiation. Patients who have autoimmune diseases such as diabetes or lupus, or who have certain rare genetic diseases need to be monitored carefully or avoid radiation altogether.

Even beyond these obvious signs, some patients suffer disfiguring, disabling or extremely painful effects. These may include wounds that don’t heal, skin burns so severe they require plastic surgery, or brain damage. Past attempts to identify these patients by screening the cancer cells themselves have failed, according to Chu. In his study, published in this week’s online edition of the Proceedings of the National Academy of Sciences, Chu and colleagues describe 24 genes that can be used to single out these patients for alternate therapies or lower radiation doses.

Chu said screening blood rather than cancer cells means the test would be more accessible to patients. “To be most useful it had to be done on peripheral blood and with a small number of genes,” he said.

Chu, whose research revolves around how cells repair damaged DNA, thought that patients who respond poorly to radiation might have cells that don’t properly recognize or repair radiation-induced DNA damage. These cells may turn on different genes, or the same genes at different levels, compared with normal cells exposed to radiation.

A group of graduate students and medical students consisting of Kerri Rieger, Wan-Jen Hong, Virginia Goss Tusher and Jean Tang tested this idea in blood samples taken from 57 cancer patients who had recently received radiation treatment. Of these, 14 patients had unusually severe radiation toxicity. The students used a gene microarray, which provides a snapshot of gene activity, to analyze which genes were active in blood cells.

In the initial analysis, Chu said the group couldn’t identify genes that were consistently different between patients who did and didn’t suffer serious side effects. He worked with Robert Tibshirani, PhD, professor of health research and policy, to develop a new statistical method of analyzing the microarray data. With this improved analysis, the group found 24 genes that behaved differently in patients who suffered radiation toxicity.

When Chu and his colleagues tested the patients’ blood samples for these 24 genes, they identified nine of the 14 people with severe reactions. Of the remaining five patients, two were later found to have been treated with new approaches that carried high risks for toxicity. That left only three of 14 patients who the test failed to identify. Most important, the test did not mistakenly pinpoint any of the other patients.

Knowing which patients may have severe radiation toxicity could make treatment decisions easier. For cancers of the breast or prostate, Chu said surgical options can be as effective as radiation. “If you knew one of the options carried a big risk, that might alter your decision,” he said.

For other cancer patients, radiation may be the best treatment. However, Chu added that patients at risk for high toxicity may also have cancers that die in response to much lower radiation doses. In such cases, radiation – though at greatly reduced doses – may still be an option.

Those who don’t have severe radiation toxicity may also benefit from this study. “If you eliminate those patients with toxicity you may be willing to use higher doses for the remaining patients,” Chu said. He said doses are set by what an average person can handle. If patients are treated individually rather than as averages, many could receive higher, more effective doses.

Chu said that before personalized treatment becomes possible, researchers must validate the 24-gene test on a larger number of samples. A biotech company must also commercialize the screen and make it available to medical labs.


Stanford University Medical Center integrates research, medical education and patient care at its three institutions – Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children’s Hospital at Stanford. For more information, please visit the Web site of the medical center’s Office of Communication & Public Affairs at mednews.stanford.