Thursday, November 30, 2006

Bortezomib and dexamethasone in MM and renal failure

Malani AK, Gupta V, Rangineni R.

Hematology and Medical Oncology, Heartland Regional Medical Center, St. Joseph, MO, USA

Multiple myeloma (MM) associated with renal failure carries a worse prognosis when compared with MM without renal failure. Bortezomib, a reversible proteosome inhibitor, is a new drug indicated for the treatment of refractory or relapsed myeloma. Published data on the use of bortezomib in patients with myeloma and renal failure are few. We report our experience with bortezomib and dexamethasone in 3 previously untreated and 1 relapsed patient with MM and renal failure. All patients achieved rapid improvement in their renal function as measured by serum creatinine levels with only 1-2 cycles of bortezomib (+/- dexamethasone), 3 of 4 patients had a near complete response and 1 patient had a partial response. The rapid reversal of renal dysfunction with bortezomib (+/- dexamethasone) treatment may be an effective strategy to prevent end stage renal failure in MM, thereby improving the morbidity and mortality in this otherwise poor prognosis subset of patients with myeloma.

Copyright 2006 S. Karger AG, Basel

PMID: 17119326 [PubMed - in process]

Monday, November 20, 2006

Image-guided radiovirotherapy for multiple myeloma using a recombinant measles virus

The Edmonston vaccine strain of measles virus (MV-Edm) propagates efficiently in a broad range of human tumor cells, killing them selectively. However, the oncolytic potency of MV-Edm in different human tumor xenograft therapy models is highly variable and there is no convenient way to map the distribution of virus-infected tissues in vivo. To enhance the oncolytic potency of MV-Edm against radiosensitive malignancies and to facilitate noninvasive imaging of infected tissues, we generated a recombinant MV-Edm encoding the human thyroidal iodide symporter (NIS). MV-NIS replicated almost as efficiently as unmodified MV-Edm, and human tumor cells efficiently concentrated radioiodine when infected with MV-NIS. Intratumoral spread of MV-NIS was noninvasively demonstrated by serial gamma-camera imaging of iodine-123 (123I) uptake both in MV-sensitive KAS-6/1 myeloma xenografts, which regressed completely after a single intravenous dose of MV-NIS, and in MM1 myeloma xenografts, which were unresponsive to MVNIS therapy. However, MV-resistant MM1 tumors regressed completely when 131I was administered 9 days after a single intravenous injection of MV-NIS (radiovirotherapy). 131I alone had no effect on MM1 tumor growth. While the potential hematopoietic toxicity of this new therapy requires further evaluation, image-guided radiovirotherapy is a promising new approach to the treatment of multiple myeloma, an incurable but highly radiosensitive plasma cell malignancy. Testing in other radiosensitive cancers is warranted.

Molecular Medicine Program, Mayo Clinic and Foundation, Rochester, MN 55905, USA.

PMID: 14604966 [PubMed - indexed for MEDLINE]

Trojan Horse halts bone metastasis in mice

A novel vascular targeting agent completely prevented the development of bone tumors in 50 percent of the mice tested in a preclinical study, providing early evidence that it could treat, or thwart, growth of tumors in bone.

Researchers at The University of Texas M. D. Anderson Cancer Center reported in the journal Cancer Research that this "Trojan Horse" agent, VEGF121/rGel, stopped specialized cells within the bone from chewing up other bone material to make room for the implanted tumor to grow.

Although this study tested the ability of VEGF121/rGel to halt the growth of human prostate cancer cells in the bones of mice, investigators say it likely could help prevent the growth of other cancers in bones such as breast, multiple myeloma, lung and renal cell.

"Many tumors invade bone in the same way, so these findings suggest it may be possible to shut down this process regardless of the tumor type," says the study's lead author, Michael G. Rosenblum, Ph.D., professor in the Department of Experimental Therapeutics. "If that could be done - and we are a long way from determining if it is possible - we may be able to offer the first treatment that specifically targets bone metastasis."

The study also revealed critical information about the role of vascular endothelial growth factor (VEGF) in the development of tumors in bone, says Rosenblum. VEGF is a signaling protein involved in the creation of new blood vessels, but in this study the researchers found that it plays a surprising role in the remodeling of bone tissue.

In the normal maintenance of bones, a balance exists between activity of cells known as osteoclasts, which break down and resorb bone matrix, and osteoblasts, which form new bone. Researchers know that tumor cells that metastasize to bones release VEGF, but what they did not know is whether the protein interrupted bone maintenance or promoted growth of blood vessels to feed the neophyte cancer, Rosenblum said

To find out, Rosenblum designed an experiment with VEGF121/rGel, an agent he and his colleagues began to develop several years ago. They created the drug by fusing the smallest of VEGF proteins (VEGF 121) to a genetically engineered toxin, gelonin, derived from a plant that grows wild in
India, and used bacteria to produce the fusion protein. The agent is designed to enter new blood vessel cells in tumors through expressed VEGF receptors and, once inside, the "Trojan Horse" toxin destroys the cell, disrupting the ability of tumors to form blood vessels to supply the nutrients they need to grow. Animal studies previously conducted by the researchers have shown that the protein can selectively destroy blood vessels feeding human solid tumors.

In this study, investigators implanted human prostate cancer cells, which are highly metastatic to bone, directly into the leg bone marrow of experimental mice in order to simulate a bone metastasis. A week later, they treated the animals with five staggered doses of VEGF121/rGel delivered through intravenous injections.

Half of the treated mice did not develop any bone tumors, Rosenblum says. "There was no evidence of cancer growth," he says, adding, "We don't know why the treatment didn't work in the other half of the mice, but we may have started therapy too late."

Rosenblum and his research team then found that VEGF121/rGel dramatically reduced the number of osteoclast cells in the leg bones and further research demonstrated that pre-osteoclast like cells, known as monocytes, had been expressing a receptor, Flt-1, designed to latch on to the VEGF protein secreted by cancer cells.

When activated by maturation factors including VEGF, the pre-osteoclasts differentiated into mature osteoclasts and chew up bone tissue, providing the tumor new space to grow. The mature osteoclast cells themselves do not express the Flt-1 receptor.

According to Rosenblum, the VEGF121/rGel agent entered the immature cells via the Flt-1 receptor and destroyed them, shutting down tumor growth. "This was a surprise to us," he says. "We had not expected these cells to be killed at all because we knew, through our earlier experiments, that VEGF121/rGel destroyed blood vessels by entering a different cell surface receptor, one which is not expressed on pre-osteoclasts."

Thus, in the bone, VEGF121/rGel may be working through two different VEGF receptors. It stops the bone destruction needed for the cancer to grow and may inhibit blood vessel growth to the metastasized tumor, Rosenblum says.

"The fact that this form of VEGF targeting works on different cell receptors in blood vessels and in bone cells is a unique finding that could be clinically significant, not only to treating cancer but other bone disorders," he says. "In the least, this study helps us understand more about how VEGF operates inside the body and how it is involved in bone remodeling."

Rosenblum said that phase I human clinical trials testing VEGF121/rGel are expected to open shortly at M. D. Anderson.

Dendritic cells stimulate cancer-cell growth

Since their discovery at Rockefeller University some 30 years ago, dendritic cells have been recognized as key players on the immune-system team, presenting antigens to other immune cells to help them respond to novel insults. Now, Rockefeller scientists have shown that dendritic cells also have other, non-immune actions, and may in fact directly modify the biology of some types of cancer cells. The results, reported recently in the Journal of Experimental Medicine, begin to clarify how the complex microenvironment of tumors promotes or inhibits their growth, which could be useful for devising novel cancer treatments.

“Tumors reside in a very complex environment that includes many, many kinds of cells,” says Madhav Dhodapkar, head of Rockefeller’s Laboratory of Tumor Immunology and Immunotherapy. “Cancer is not a disease just of the cancer cell, but of that cell in the context of everything else around it.” Dendritic cells, in particular, are abundant in myeloma and other tumors. They are attracted by chemical signals secreted by tumor cells, and were suspected of modulating the immune system so that it tolerates tumors instead of attacking them.

Dhodapkar’s research focuses on multiple myeloma, the unchecked proliferation of plasma cells in bone marrow. These immune cells are the final developmental stage of B cells, and are tuned to respond to specific antigens. The team used specialized culture systems to explore how individual components of the microenvironment influence cancer development. Ordinarily, only about one tumor cell out of a hundred forms a colony in these cultures, but when the scientists introduced progressively more dendritic cells, the number of colonies progressively increased, ultimately multiplying by a factor of more than 10. Previous research had found that macrophages, a cousin of dendritic cells, directly affect tumor-cell growth, but the effect had never been observed with dendritic cells.

The dendritic cells also caused some tumor cells to go “backward” in development, resuming production of a chemical marker that had been shut off as they progressed from B cells to plasma cells. “These data suggest that the differentiation state of myeloma cells may be plastic, and capable of change in response to the microenvironment,” Dhodapkar explains. “This plasticity could be important in understanding how tumors develop.”

The researchers also identified two chemical signaling pathways by which the dendritic cells influence tumor cells, suggesting that complementary molecules on the surfaces of the two types of cells act only when the cells are in direct contact.

The supporting role of dendritic cells in tumors is also providing new insights into treatment. In a followup study in the British Journal of Haematology, Dhodapkar's team reports that a well-known myeloma drug, bortezomib, disrupts the interaction between tumor and dendritic cells in culture, and also kills the problematic dendritic cells. “In myeloma we are learning that both tumors and their environment need to be targeted for effective therapies,” he says.

Journal of Experimental Medicine 203(8): 1859-1865 (August 2006)
British Journal of Haematology Online: October 24, 2006

Tuesday, November 07, 2006

Medarex and PacMab to develop therapeutic antibodies for Multiple Myeloma

Medarex and PacMab will develop Mab-based therapies for blood cancers, under a collaborative agreement between the two firms. "Initially we will focus on the most prevalent form of multiple myeloma,” says Alan Liddle, CEO of PacMab. “At the same time, we will be developing our pipeline of additional drug therapies using our monoclonal antibody technology aimed at other blood disorders with unmet clinical needs."

The companies plan to begin clinical trials for PacMab’s existing antibody therapeutic in 2007. Through a collaborative development program, the companies intend to use Medarex' UltiMAb Human Antibody Development System® to generate fully human antibodies for novel disease targets.

Monday, November 06, 2006

Long-term therapy In the battle against Multiple Myeloma

There is no known cure for multiple myeloma, so its diagnosis means high-dose chemotherapy followed by repeated treatments with each relapse of the cancer -- a watch and wait approach. A new approach of providing patients with continuous therapy to keep the cancer at bay was explored by a team of international researchers. Their findings will be published in the November 15, 2006, issue of Blood, the official journal of the American Society of Hematology.

"We have been anxiously waiting for the results of this study in the multiple myeloma community, as the issue of maintenance therapy has never been resolved," said Joseph Mikhael, MD, a hematologist at the Princess Margaret Hospital in Toronto. "The results are impressive in favor of ongoing treatment of patients with multiple myeloma, and are quite likely going to change the standard of care."

In multiple myeloma, an overgrowth of abnormal cells in the bone marrow leads to the painful destruction of bone. In this study, pamidronate, a drug often used early in the treatment of multiple myeloma to help protect against bone damage, was for the first time studied as a maintenance therapy. Its use alone was compared against its combination with thalidomide, a drug known to inhibit the growth of myeloma cells. A third set of patients in the study did not receive any maintenance therapy, the current standard of care in this disease.

A total of 597 patients participated, and measures of success included the likelihood of the cancer coming back, the risk of an adverse skeletal event (such as a bone lesion), and the patients' overall survival probability. Using these measures:

* The results of using pamidronate alone compared with going without

maintenance therapy were similar. The three-year probability of the

patients remaining relapse-free was 38 percent without maintenance

therapy and only somewhat better -- at 39 percent -- with pamidronate

alone. The addition of thalidomide significantly improved these odds to

51 percent.

* The use of pamidronate did not decrease the number of bone events as

anticipated, and there was no significant difference in the number of

these events between the three treatment groups.

* The chance of overall survival four years after study enrollment in the

pamidronate-thalidomide group was 87 percent. Patients in the

pamidronate-alone arm had a 74 percent survival probability compared

with those not receiving therapy at 77 percent.

Thalidomide, however, is not for everyone. The drug was originally dosed at 400 mg per day, but after 15 months, the median dose was decreased by half because of drug-related toxicity. Thalidomide was discontinued in 39 percent of the patients taking the drug due to side effects such as numbness, tingling, or pain in the hands and feet, fatigue, and constipation. In contrast, only 4 percent of patients discontinued pamidronate.

Patients most likely to benefit from the addition of thalidomide to maintenance therapy were those whose responses to the original chemotherapy were not as successful, and those who did not have a chromosome 13 deletion, an abnormality found in about 15-20 percent of patients with multiple myeloma and one that is associated with a poorer prognosis.

"Thalidomide shows great promise for keeping multiple myeloma in check after chemotherapy," said Michael Attal, MD, PRD, lead author of the study and Head of the Department of Hematology at Hopital Purpan in Toulouse, France. "If measures can be taken to mediate the toxicity of the drug, or if only those who would get the most benefit from it are treated, this could be an effective long-term therapy for many patients."

The American Society of Hematology (http://www.hematology.org) is the world's largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems, by promoting research, clinical care, education, training, and advocacy in hematology.

Blood, the official journal of the American Society of Hematology, is the most cited peer-reviewed publication in the field. Blood is issued to Society members and other subscribers twice per month, available in print and online at http://www.bloodjournal.org.

Source: American Society of Hematology

Thursday, November 02, 2006

Resveratrol: Increases life span of mice

Small Molecule Increases Lifespan and "Healthspan" of Obese Mice

Risk of Death Cut By 31 Percent for Obese Mice Treated with Compound, and Treated Mice Seen Living as Long as Lean Mice

In Obese Mice, Molecule Reversed Nearly All Pathways Activated In Mice By High Calorie Diets

Findings Suggest Broad Implications for the Treatment of Age-related Diseases, Including Diabetes and Heart Disease

BOSTON-November 1, 2006-Researchers have used a single compound to increase the lifespan of obese mice, and found that the drug reversed nearly all of the changes in gene expression patterns found in mice on high calorie diets--some of which are associated with diabetes, heart disease, and other significant diseases related to obesity. The research, led by investigators at Harvard Medical School and the National Institute on Aging, is the first time that the small molecule resveratrol has been shown to offer survival benefits in a mammal. The study is reported in the November 1 advanced online edition of Nature.

"Mice are much closer evolutionarily to humans than any previous model organism treated by this molecule, which offers hope that similar impacts might be seen in humans without negative side-effects," says co-senior author David Sinclair, HMS associate professor of pathology, and co-director of the Paul F. Glenn Labs for the Biological Mechanisms of Aging.

"After six months, resveratrol essentially prevented most of the negative effects of the high calorie diet in mice," said Rafael de Cabo, Ph.D., the study's other co-senior investigator from the National Institute on Aging's Laboratory of Experimental Gerontology, Aging, Metabolism, and Nutrition Unit. "There is a lot of work ahead that will help us better understand resveratrol's roles and the best applications for it."

Resveratrol is found in red wines and produced by a variety of plants when put under stress. It was first discovered to have an anti-aging properties by Sinclair, other HMS researchers, and their colleagues in 2003 and reported in Nature. The 2003 study showed that yeast treated with resveratrol lived 60 percent longer. Since 2003, resveratrol has been shown to extend the lifespan of worms and flies by nearly 30 percent, and fish by almost 60 percent. It has also been shown to protect against Huntington's disease in two different animal models (worms and mice).

"The "healthspan" benefits we saw in the obese mice treated with resveratrol, such as increased insulin sensitivity, decreased glucose levels, healthier heart and liver tissues, are positive clinical indicators and may mean we can stave off in humans age-related diseases such as type 2 diabetes, heart disease, and cancer, but only time and more research will tell," says Sinclair, who is also a co-founder of Sirtris, a company with an author on this paper and which is currently in a phase 1b trial in humans with diabetes using an enhanced, proprietary formulation of resveratrol. [Harvard has license and equity interests with Sirtris, which is not a public company.]

Investigators identified resveratrol while looking for compounds that activate Sir2, an enzyme linked to lifespan extension in yeast and other lower organisms. For the last 70 years, scientists have been able to increase the lifespan of a variety of species by reducing their normal food consumption by 30 to 40 percent - a diet known as calorie restriction. Through this research, scientists identified Sir2 as a key contributor to life extension. Without Sir2, for example, fruit flies see none of the benefits from either calorie restriction or treatment by resveratrol. The mammalian version of the Sir2 gene is SIRT1, which has the same enzymatic activity as Sir2, but modifies a wider variety of molecules throughout cells. Indicators in this study show that resveratrol might also be activating SIRT1 in mice, as well as other known longevity pathways.

How the Study Was Done
Survival Benefit
Reversing Genetic Pathways Triggered by High Calorie Diet
Improved Health Biomarkers: Glucose and Insulin
Organ Protection: Heart and Liver
Links to Calorie Restriction Lifespan Model
Links to SIRT1

How the Study Was Done
This study examined three groups of mice, one on a standard diet (SD), another on a high calorie diet (HC) with 60 percent of calories coming from fat, and a third group of mice on the same high calorie diet but also treated with resveratrol (HCR). At middle age, or roughly 52 weeks of life, the researchers put the mice on the different diets.

Survival Benefit
At 60 weeks of age, the survival rates of HC and HCR fed mice groups began to diverge and remained separated by a three to four month span. At 114 weeks of age, 58 percent of the HC fed mice had died, compared to 42 percent of the HCR and SD groups. Presently, the team has found resveratrol to reduce the risk of death from the HC diet by 31 percent, to a point where it is not significantly increased over the SD group.(Note: Given that mice are still living, final calculations can't be made.) "The median lifespan increase we are seeing is about 15 percent at this point," says Sinclair. "We won't have final lifespan numbers until all of the mice pass away, and this particular strain of mouse generally lives for two-and-a-half-years. So we are around five months from having final numbers, but there is no question that we are seeing increased longevity.

The team also found that the HCR fed mice had a much higher quality of life, outperforming the HC fed mice on motor skill tests. "The mice on resveratrol have not been just living longer," says Sinclair. "They are also living more active, better lives. Their motor skills actually show improvement as they grow older."

Reversing Genetic Pathways Triggered by High Calorie Diet
The research team also wanted to see if resveratrol could reverse the changes in gene expression patterns triggered by high calorie diets. Using liver tissue of five mice at 18 months of age from each group, the team performed a whole-genome microarray and identified which genes were turned on or off. The researchers then used a database generated by the Broad Institute that groups individual genes into common functional pathways to see where there were major differences.

"We made a striking observation," says Sinclair. "Resveratrol opposed the effects of high caloric intake in 144 out of 153 significantly altered pathways. In terms of gene expression and pathway comparison, the resveratrol fed group was more similar to the standard diet fed group than the high calorie group."

Improved Health Biomarkers: Glucose and Insulin
In humans, high calorie diets can increase glucose and insulin levels leading to diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. In the HC fed mice, researchers found biomarkers that might predict diabetes, including increased levels of insulin, glucose and insulin-like growth factor-1 (IGF-1). Conversely, the HCR fed group had significantly lower levels of these markers, paralleling the SD group. For example, a standard diabetes glucose test on the HCR fed group found considerably higher insulin sensitivity, meaning the HCR group had a lower disposition toward diabetes than the HC fed group. Lower insulin levels also predict increased lifespan in mice.

Organ Protection: Heart and Liver
Three pathologists examined heart tissue from the SD, HC, and HCR mice, and while not knowing which organ belonged to which mouse group, they looked for subtle changes in the abundance of fatty lesions, degeneration and inflammation. On a relative scale of 0-4, the assessment produced mean scores of 1.6 for the SD group, 3.2 for the HC group, and 1.2 for the HCR group.

The researchers also found that the livers of mice at 18 months of age on the HC diet were greatly increased in size and weight. Liver tissue studies of these mice showed a loss of cellular integrity, and a build-up of lipids, which is common to high fat diets. In contrast, the HCR group had normal, healthy livers.


Links to Calorie Restriction Lifespan Model
The researchers also looked for metabolic ties to resveratrol's impact: pathway changes that mimicked those caused by calorie restriction. They examined AMP-activated kinase (AMPK), a metabolic regulator that promotes insulin sensitivity and fatty acid oxidation. It's been shown in previous work that the lifespan of worms has been extended by the addition of copies the AMPK gene, and chronic activation of AMPK is seen on calorie-restricted diets. The researchers examined the livers of the HCR fed group and found a strong tendency for AMPK activation, as well as two downstream indicators of its activity.

Calorie restriction and exercise have also been previously shown to increase the number of mitochondria in the liver. Mitochondria generate energy in cells. Through electron microscopy, investigators showed that the livers of the HCR fed mice had considerably more mitochondria than the HC group, and were not significantly different from those of the SD group.

Links to SIRT1
The team also asked if SIRT1 was activated by resveratrol in mice, as Sir2 is in lower organisms. To determine this, they looked at the amount of a specific chemical modification (acetylation) on the molecule PGC-1alpha. Removal of the "acetyl" chemical groups on PGC-1alpha activates this protein so that it can turn on certain genes that generate mitochondria and turn muscle into the type suited for endurance. The only enzyme known to remove the acetyl chemical groups on PGC-1alpha is SIRT1, and therefore the activity of PGC-1alpha is one of the most reliable and specific markers of SIRT1 activity in mammals. The research team found that levels of PGC-1alpha were three-fold lower in the HCR fed mice than in the HC mice, consistent with what would be expected when SIRT1 was being activated by resveratrol.

"This work demonstrates that there may be tremendous medical benefits to unlocking the secrets behind the genes that control our longevity," says Sinclair, "No doubt many more remain to be discovered in coming years."

This study was supported by Paul F. Glenn and the Glenn Foundation for Medical Research, the U.S. National Institutes of Health and the National Institute on Aging, the Ellison Medical Research Foundation, the American Heart Foundation, and the American Diabetes Association.

Contact: John Lacey, Harvard Medical School, 617-432-0442 public_affairs@hms.harvard.edu

Source: http://web.med.harvard.edu/sites/RELEASES/html/11_1Sinclair.html

Resveratrol - Protein extends life - Harvard study

For those of you who want to live longer, you're getting closer to having your cake and eating it. You can even add a glass of wine.

Last year, David Sinclair and his colleagues at Harvard Medical School extended the lives of yeast cells by feeding them a protein known as Sir2. This year, he fed a closely related protein to tiny worms and fruit flies. The worms lived as much as 14 percent longer, the flies as much as 23 percent. If it works in humans, that would extend our roughly 83-year lives to about 95 or 102.

The protein works on human cells growing in a test tube, but will it work on baby boomers trying to live the good life longer? "It's pure speculation at this point, but we now have the first molecule that extends life in species, from fungi to flies," Sinclair says. "If you arrange all the species on Earth on a scale of one to 10, yeast is a one, humans a 10, flies and worms are a nine. So we've come a long way."

The protein molecule, in a form known as resveratrol, is sold by dozens of health-food companies. "About 10,000 people in this country take this product with no apparent side effects," Sinclair notes. However, the pill has not been approved by the U.S. Food and Drug Administration so people run an unknown risk by taking it.

Harvard Medical School rules prevent Sinclair from recommending the product, or admitting if he takes it. "However," he says, "I know a number of scientists who think resveratrol is their best shot. Others satisfy themselves with a glass of red wine," which contains the compound. (Fortunately, the extent of the effect does not depend on the price of the wine.)

Such compounds, known as STACs, activate the same natural proteins as severe calorie restriction, long known as a way to gain extra years. Reliable tests have shown that cutting calories extends the lives of yeast cells, worms, and flies. Now, Sinclair has shown these species can eat all they want and live longer with the help of STACs. The experiments he did with his colleagues are described in the July 14 issue of Nature.

Calorie restriction is embraced by a small group of people in this country who hope to have healthful (if not full) lives for 100 years or more by reducing their calorie intake by as much as 30 percent. A few of these people are also taking high doses of resveratrol. Of course, there is no way yet to know if it's all going to be worth it.

Brian Delaney, president of an organization that tracks those trying to live longer by severely restricting their diets, gave up the effort himself. In his 30s, he found that lifestyle too tough to put up with for 60 to 70 years. Delaney now takes resveratrol.

Side benefits

Calorie cutting and resveratrol seem to have other benefits.

Two Harvard studies, published in 1997, concluded that being 15 to 20 percent underweight lowers the risk of death from all causes. Other credible research found that eating significantly less food lowers blood pressure, increases so-called "good" cholesterol, and lessens chances of dying from cancer, heart disease, and stroke.

Worms and rats put on severely restricted diets show a high rate of infertility, but those fed STACs don't have that problem.

Resveratrol could also turn out to be an effective drug for preventing some cancers. The National Cancer Institute is testing it on people with a high risk of colon cancer. Two other STACs - quercetin and fisetin - have proven safe enough to be tested as anti-diabetes drugs.

Sinclair has started a company, called Sirtris Pharmaceuticals, to make a variety of synthetic STACs. The company hopes to start testing the drugs on diseases of aging, like diabetes, in a year or two. After that, it might be on aging itself. "At least, that's what we're hoping," he says.

"We have something that extends the life of every species it's given to," Sinclair enthuses. "We're 50 years ahead of where I thought we would be 10 years ago."

Source: Harvard News, July 14, 2004

http://www.news.harvard.edu/gazette/daily/2004/07/14-yeast.html

Pterostilbene: cancer fighter

Recent research by Agricultural Research Service (ARS) scientists and cooperators has fortified the standing of pterostilbene, a berry and grape compound cited for its health benefits, as a cancer inhibitor.

Scientists found that the compound strongly suppresses a type of an enzyme that activates cancer-causing processes.

Researchers at the ARS Natural Products Utilization Research Laboratory in Oxford, Miss., targeted an enzyme called cytochrome P450, which sets off a variety of compounds—known as procarcinogens—that can turn substances such as cigarette smoke and pesticides into cancer-causing agents. Cytochromes are a factor in people’s varying responses to drugs and toxins entering their bodies.

Numerous animal studies have focused on pterostilbene (pronounced "tare-o-STILL-bean") and its potential benefits to human health. This includes work showing that pterostilbene can help lower cholesterol and prevent heart disease, and that the compound is present in a genus of shrubs that includes many types of berries, including blueberries.

Studies that found that the compound is a powerful antioxidant that shows cancer-fighting properties similar to those of resveratrol. Indeed, pterostilbene is a derivative of resveratrol, a compound found in large quantities in the skins of red grapes that's known for its cardiovascular and cancer-fighting benefits.

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