Aspirin should not routinely be used to prevent cardiovascular events in diabetics

Aspirin should not be routinely prescribed to diabetics for the prevention of heart attack and stroke, say researchers. ... Continue Reading

Antipsychotic Drugs of Little Benefit to Alzheimer's Patients

, (HealthDay News) -- The continuing use of antipsychotic drugs provides no cognitive or neuropsychiatric benefit for Alzheimer's patients, a British study concludes.

Researchers at King's College Hospital in London studied 165 patients who were already being treated with antipsychotic drugs. The patients were divided into two groups -- one continued treatment with the drugs, while the other group stopped treatment.

The patients were assessed six and 12 months later, and the researchers found no differences between the two groups in terms of cognitive decline or in the number of neuropsychiatric problems.

Patients with severe neuropsychiatric problems at the start of the study may have derived some benefit from continued drug therapy, but this difference was not statistically significant, the researchers said.

While these findings suggest that continued use of antipsychotic drugs offers no benefits for Alzheimer's patients, this was a small study, the study authors noted. More research is needed to improve management of these patients, they added.

The study appears in the cuurent issue of PLoS Medicine.

Almost all older dementia patients have some neuropsychiatric symptoms, such as agitation, aggression and psychosis. Antipsychotics are often used to manage or control these symptoms, but there are safety concerns, including increased risk of stroke, sedation, edema, chest infections and parkinsonism. Prolonged use of antipsychotics may also lead to a worsening of cognitive decline.

More information
The U.S. National Institute on Aging has more about Alzheimer's medications.

Most Older Americans Living Longer and Better

(HealthDay News) -- Older Americans are living longer than ever and enjoying better health and financial security, a new report finds.

Yet there continue to be lingering disparities between racial and ethnic groups.

In 2006, there were an estimated 37 million Americans 65 and older -- 2 percent of the population. By 2030, it's estimated at 71.5 million people will be 65 and older -- almost 20 percent of the population, according to the report, Older Americans 2008: Key Indicators of Well-Being.

"This report comes at a critical time," Edward Sondik, director of the National Center for Health Statistics, said Thursday in a prepared statement. "As the baby boomers age and America's older population grows larger and more diverse, community leaders, policymakers and researchers have an even greater need for reliable data to understand where older Americans stand today and what they may face tomorrow."

The report examined five broad areas of well-being: economics, health status, health risks and behaviors and health care.

Even though life expectancy for Americans continues to increase for those 65 years of age, it is lower than in countries such as Canada, France Japan and Sweden. For example, Japanese women 65 years of age live 3.2 years longer than women in the United States. Among men, the difference is 1.2 years, according to the report.

In terms of overall health, key indicators such as smoking rates, flu and pneumonia vaccinations and screening for breast cancer have improved but have leveled off in recent years.

As for chronic conditions, women reported higher levels of arthritis compared with men. Men reported higher levels of heart disease and cancer. Among African-Americans, there were higher levels of high blood pressure and diabetes compared with whites. Hispanics reported higher levels of diabetes than did non-Hispanic whites.

The number of people 65 and older who are obese increased from 22 percent in 1988-1994 to 31 percent in 2000-2006. At the same time, there was no significant change in the number of older people who engaged in physical activity. In fact, most days Americans 65 and older reported spending half their time watching television. Those 75 and older, however, spent more time reading and relaxing and thinking, compared with people 55 to 64 years old.

In addition, as people aged, they spent less time visiting friends or attending social functions. Socializing declined from 13 percent of those 55 to 64 to 10 percent of those 75 and older. And, time spent devoted to sports, exercising, recreation and travel also declined with age, according to the report.

Older people's ability to obtain, process and understand health information or services -- called health literacy -- declined with age. Thirty-nine percent of people 75 and older had below basic health literacy, compared with 23 percent of people ages 65 to 74, and 13 percent of people 50 to 64.

Escalating health-care costs, particularly for prescription drugs, also affected older Americans: From 1992 to 2004, costs rose from $8,644 to $13,052. In 2004, prescription drugs made up 61 percent of out-of-pocket health costs for older Americans, the report found.

These costs are expected to be mitigated by the Medicare Part D prescription drug benefit. From 2006 to 2007, the number of people enrolled in the program increased from 18.2 million to 19.7 million, according to the report.

Despite these rising costs, many older Americans are more economically secure. From 1974 to 2006, the number of older Americans living below the poverty line decreased from 15 percent to 9 percent. In addition, the number of older Americans with higher incomes increased from 18 percent to 29 percent.

However, racial disparities existed, with net worth among whites 65 and older six times that of older African-Americans. And, more older Americans, particularly women, continued to work after 55.

The report was prepared by the Federal Interagency Forum on Aging-Related Statistics, which represents 15 agencies responsible for collecting data on aging. The last report was released in 2006.

One expert thinks that lack of physical activity and lack of social activity are the two biggest factors affecting the health of older Americans.

"It's kind of sad when you think about all the money and all the effort that has gone into physical activity awareness and that the actual amount has not increased over the last 10 years," said Colin Milner, chief executive officer of the International Council on Active Aging. "What that is saying is, we're doing something wrong."

Milner thinks new ways of getting people to be more active are needed. People don't realize that only a little physical activity can have a major impact on their health, he said.

"People see athletic activity, and they say: 'Forget it. I can't do that, I'm old,' " Milner said."We can save roughly $77 billion in health-care costs by increasing physical activity," he noted.

Milner said he's also concerned that older people spend too much time watching TV and becoming socially isolated.

"How long is it going to be before we engineer socialization out of our lifestyle," Milner said. "By 2020, depression will be the second-leading cause of premature death according to the World Health Organization. And now, you're taking socialization out of a lifestyle."

More information
To see the full report, visit the U.S. Federal Interagency Forum on Aging-Related Statistics.

Diabetic mice cured with drugs

US scientists have managed to rid diabetic mice of the effects of the disease using a cocktail of drugs.
The mice, who had type 1 diabetes, started producing their own insulin after taking a mixture of four drugs.

Previously the same team at Harvard University had only been able to stop the destruction of the cells which make insulin, not regenerate them.

But in a study reported in the New Scientist, they say adding another drug to the original cocktail did just that.

They now hope to start trials in humans.

Type 1 diabetes is usually managed through regular injections of insulin and until now, research into a cure has focused on transplanting the pancreatic beta cells which produce the hormone from donors.

However this is complicated - both because of the difficulty in finding a donor and the problems of rejection - so regenerating a person's own cells is seen as far better option.

Extra enzyme

Last year, Dr Terry Strom and his team demonstrated that they could stop the on-going destruction of insulin-producing beta cells in mice using a combination of three drugs, although they were unable to regenerate the cells.

However, when they added an extra ingredient - an enzyme called alpha 1 anti-trypsin - a significant rise in the number of beta cells was seen.

It is thought this extra drug may ease the inflammation of pancreas, a key feature of the disease.

"It would appear that by altering the inflammatory state that surrounds this autoimmune disease, you can create an environment that enables expansion of the beta cell mass," said Dr Strom.

He added that it was too early to say whether the beta cells which had stopped making insulin had recovered, or whether new ones were being produced.

http://news.bbc.co.uk/2/hi/health/7267586.stm

Dr Iain Frame, director of research at Diabetes UK said: "This could potentially be very important research in finding a better treatment for diabetes.

"More research is needed as initial studies have only been conducted in mice, but Diabetes UK is pleased that clinical trials are planned and look forward to hearing the results."

Cure hope over diabetes therapy

A pioneering treatment for diabetes is being rolled out across the country with experts believing it could eventually lead to a cure.
Six centres are receiving nearly £10m of government funding to offer transplants of insulin-producing cells.

The technique has been used on a handful of patients already to reduce the risks of coma-inducing blood sugar attacks in people with type 1 diabetes.

Experts hope the therapy can be refined in the future to offer a complete cure.

People with type 1 diabetes do not produce enough insulin, which means they have to rely on injections of the hormone.


There are about 250,000 people with the condition, which usually develops in childhood and is unconnected with lifestyle factors such as obesity unlike the type 2 version of the disease.

The procedure involves obtaining cells - known as islet cells - from the pancreas of a dead donor and injecting them into the patient's liver.

Once there, the cells get to work producing insulin.

The major international breakthrough was announced in 2000 in Canada but the first UK transplant was carried out by London's King's College Hospital in 2002.

Since then 12 patients have undergone the therapy across the country.

It has been used on people at risk of hypoglycaemia - low blood sugar that can lead to coma-inducing attacks.

The treatments give protection against hypoglycaemia and in some of the patients have freed them from needing daily insulin injections for a period.


However, the patients need to take immunosuppressant drugs for the rest of their lives and it is likely re-transplants will be likely in the future as doctors do not expect the hypoglycaemia protection to last for ever.

The government-funding will mean many more patients will be able to benefit from the technique, with up to 20 transplants planned in the first year before the numbers are gradually built up to about 80.

From April, the Department of Health will fund two laboratories - in London and Oxford - to receive donor pancreases and prepare the cells for transplantation.

The labs will be able to provide the cells to six transplant centres based at the Oxford Radcliffe, Newcastle-up-on Tyne, North Bristol, Central Manchester, Kings College and Royal Free NHS trusts.

Extreme cases

It will mean in time the 2,000 patients at risk of hypoglycaemia will be able to get the treatment if needed.

The only alternative at the moment is to have a complete pancreatic transplant, but that is only ever done in the most extreme cases.

Professor Stephanie Amiel, a diabetes expert at King's College Hospital, said "Allowing King's and the other centres to continue to offer this life-changing treatment will have enormous benefit for those patients who are suitable for islet transplantation in its present form.

"It will also allow the UK to develop the technique to be suitable for more people with type 1 diabetes and may, in time, lead to a 'cure'."

Diabetes UK chief executive Douglas Smallwood added: "The decision to fund this programme will be life-changing for some people.

"Resolving the worst cases could save the NHS a significant amount of money, as hypoglycaemic attacks cost £15m a year in hospitalisations and ambulances alone. "
http://news.bbc.co.uk/1/hi/health/7238418.stm

Scientists Find New Receptor for H.I.V.

Government scientists have discovered a new way that H.I.V. attacks human cells, an advance that could provide fresh avenues for the development of additional therapies to stop AIDS, they reported on Sunday.The discovery is the identification of a new human receptor for H.I.V.

The receptor helps guide the virus to the gut after it gains entry to the body, where it begins its relentless attack on the immune system.The findings were reported online Sunday in the journal Nature Immunology by a team headed by Dr. Anthony S. Fauci, the director of the National Institute of Allergy and Infectious Diseases.For years, scientists have known that H.I.V. rapidly invades the lymph nodes and lymph tissues that are abundant throughout the gut, or intestines.

The gut becomes the prime site for replication of H.I.V., and the virus then goes on to deplete the lymph tissue of the key CD4 H.I.V.-fighting immune cells.That situation occurs in all H.I.V.-infected individuals, whether they acquired the virus through sexual intercourse, blood transfusions, blood contamination of needles and syringes, or in passage through the birth canal or drinking breast milk.The findings appear to provide some, if not the main, answers to how and why that situation occurs.

Dr. Warner C. Greene, an AIDS expert and the director of the Gladstone Institute of Virology and Immunology here who was not involved in the research, said the findings were “an important advance in the field.”“They begin to shed light on the mysterious process on why the virus preferentially grows in the gut,” Dr. Greene said in an interview.

Dr. Fauci, James Arthos, Claudia Cicala, Elena Martinelli and their colleagues showed that a molecule, integrin alpha-4 beta-7, which naturally directs immune cells to the gut, is also a receptor for H.I.V. A protein on the virus’s envelope, or outer shell, sticks to a molecule in the receptor that is linked specifically to the way CD4 cells home in on the gut, the researchers said.

Binding of the virus to the integrin alpha-4 beta 7 molecule stimulates activation of another molecule, LFA-1, which plays a crucial role in the spread of the virus from one cell to another. The actions ultimately lead to destruction of lymph tissue, particularly in the gut.

Several other receptor sites for H.I.V. are known. The most important is the CD4 molecule on certain immune cells; the molecule’s role as an H.I.V. receptor was identified in 1984.Two other important receptors, known as CCR5 and CXCR4, were identified in 1996. CCR5 is a normal component of human cells and acts as a doorway for the entry of H.I.V. People who lack it because of a genetic mutation rarely become infected even if they have been exposed to H.I.V. repeatedly.

“The work we did took nearly two years, and there’s little doubt that what we have found is a new receptor,” Dr. Fauci said in an interview after giving a lecture here, adding that “we certainly have to learn a lot more about it.”Scientists have sought to identify receptors because they offer targets for the development of new classes of drugs.

For example, last year the Food and Drug Administration approved for AIDS treatment a Pfizer drug, Selzentry or maraviroc, which works by blocking CCR5.Dr. Fauci said he hoped his team’s findings would encourage other scientists from different disciplines to explore new ways to attack H.I.V.

A number of experimental drugs that block the integrin alpha-4 beta-7 receptor are being tested for the treatment of autoimmune disorders. Dr. Fauci said such drugs should also be studied for their potential benefit in AIDS treatment.

Organization of new trials in the next year or so could test such drugs in animals and humans to determine their safety and effectiveness against H.I.V., Dr. Fauci said.One candidate is a drug, Tysabri or natalizumab, that is marketed for treatment of multiple sclerosis, Dr. Fauci said. Biogen/Elan makes Tysabri.

If trials for H.I.V. are successful, Dr. Fauci said, the drugs could be added to existing treatment regimens.

http://www.nytimes.com/2008/02/11/health/11aids.html?ref=health

Gene At Intersection Of Stem Cells, Immunity

A gene that "wakes up" the blood system's stem cells in times of stress also plays an important role in protecting against infection, said researchers from Baylor College of Medicine in Houston, the National Institute of Allergy and Infectious Disease and Duke University Medical School in a report that appears in the journal Cell Stem Cell.

When Dr. Margaret Goodell, professor of pediatrics and director of BCM's Stem Cells and Regeneration (STaR) Center, and her colleagues infected mice that lacked the gene interferon-inducible GTPase Lrg-47 with a bacteria akin to tuberculosis, they found that stem cells did not initiate the process of making blood cells to protect against the infection.

Stress response

"It suggests that this gene might have a role in normal blood production, but its main role is in stress response," she said. "It's really involved in recovery from a toxic drug or infection or regenerating a blood system after a bone marrow transplant."

It makes sense that a serious infection with a pathogen or disease-causing organism could require that stem cells rally to generate new blood cells to fight against the invading organisms.
"In the mice with the defective gene, the stem cells could not wake up," said Goodell. "It is the first time anyone has a shown a link between infection and activating stem cells."

"You probably have to activate the stem cells to make all your blood cells. This gene might be a link in that system," she said.

"What was surprising was that this gene was regulated by interferon gamma," she said. "These proteins are well known because they regulate the immune system."

Surprise finding

Finding the interferon-inducible GTPase Lrg-47 in stem cells was a surprise, she said. "Maybe it is a way of the immune system talking to stem cells."

Collaborating with the NIAID team helped answer the question. They had bred mice to lack the gene and shown that these mice died of an infection that normal mice could easily control. The team in Bethesda, Maryland, noted that the mice had low blood counts.

They shared their mice with the BCM team who looked at the animals' stem cell biology. The mice with the defective gene had stem cells that did not function well. Under normal conditions, they could make blood. However, when stressed by a chemical or disease-causing organism that attacked the blood cells, the stem cells did not recover quickly.

When Goodell and her colleagues tried to do a bone marrow transplant with the mice, it did not work.

"There were almost completely incapable of regenerating the blood system in another mouse," she said.

In the future, she said, she and her colleagues want to study why this gene has such an impact on stem cells. It will also help delineate the role of interferons in the cell.

Others who took part in this work include Drs. Carl G. Feng and Alan Sher of NIAID, David C. Weksberg of BCM and Dr. Gregory A. Taylor of Duke.

Funding for this work comes from the National Institutes of Health and the Leukemia and Lymphoma Society.

http://www.sciencedaily.com/releases/2008/02/080224142524.htm

Computers 'spot Alzheimer's fast'

Computers can diagnose Alzheimer's disease faster and more accurately than experts, research suggests.

University College London researchers say their work may help ensure patients are diagnosed earlier, increasing the chances of effective treatment.

Their study, published in the journal Brain, found computers can identify brain damage caused by Alzheimer's with an accuracy as high as 96%.

At present a definitive diagnosis is usually only possible after death.

Alzheimer's is caused by the build up in the brain of plaques and tangles of brain tissue filaments, which causes tissue to start wasting away.

It is currently diagnosed using a combination of brain scans, blood tests and patient interviews, but distinguishing the disease from other forms of dementia is difficult, and time consuming, and the accuracy of diagnosis is only about 85%.

The new method works by teaching a standard computer the differences between brain scans from patients with proven Alzheimer's, and people with no signs of the disease.

The two conditions can be distinguished with a high degree of accuracy on a single clinical MRI scan.

Researcher Professor Richard Frackowiak said: "The advantage of using computers is that they prove cheaper, faster and more accurate than the current method of diagnosis.

"The new method makes an objective diagnosis without the need for human intervention.
"This will be particularly attractive for areas of the world where there is a shortage of trained clinicians and when a standardised reliable diagnosis is needed, for example in drug trials."

Speed important

Professor Frackowiak emphasised that as symptoms only emerge after a considerable amount of damage has already occurred in the brain it is important to make an accurate diagnosis early to improve the chances of effectively preventing further deterioration.

He said: "The next step is to see whether we can use the technique to reliably track progression of the disease in a patient.

"This could prove a powerful and non-invasive tool for screening the efficacy of new drug treatments speedily, without a need for large costly clinical trials."

Dr Susanne Sorensen, of the Alzheimer's Society, said: "Currently, MRI imaging is not routinely used in diagnosing the diseases causing dementia.

"This paper puts a strong case for the wider use of this technique."

Dr Sorensen said it was vital the National Dementia Strategy currently being produced by the government makes early diagnosis a high priority.

Rebecca Wood, of the Alzheimer's Research Trust, said: "This promising computer aided technique could act as a second opinion to increase the accuracy of a doctor?s diagnosis.
"However, this research is in the early stages and further analysis is required to understand the full benefits and accuracy of this technique and to see if it can be used to assess the effectiveness of new drugs."

It is estimated that over 700,000 people in the UK are currently living with dementia, of which Alzheimer's is the most common form.

http://news.bbc.co.uk/1/hi/health/7258379.stm

Brain drug target discovery in MS

US researchers have found two potential targets for treating multiple sclerosis after an extensive trawl through proteins in the brain.

Comparison of 2,538 proteins from MS patients with those from healthy brains showed damage in two proteins not before linked to the disease.

In mice blocking the effects of the proteins led to reversal of symptoms, the study in Nature reported.

There are about 85,000 people with MS in the UK.

The condition is caused by a defect in the body's immune system, which turns in on itself, attacking the fatty myelin sheath which coats the nerves, leading to symptoms including blurred vision, loss of balance and, in some cases, paralysis.

Study leader Professor Lawrence Steinman said this was the first large-scale study to search for defective proteins in MS lesions in the brain.

They found a few proteins peculiar to MS brain lesions.

But two in particular - tissue factor and protein C inhibitor - showed signs of damage during the chronic active stage of the disease.

These normally participate in the control of blood clotting and in anti-inflammatory pathways. The researchers guessed that the damaged proteins might be helping the progression of MS and, by using inhibitors of the proteins found they could successfully ameliorate the disease in mice.

Treatment

Professor Steinman, from Stanford University School of Medicine in California, said the finding opened up the way for new treatments.

However, using existing drugs which interfere with the control of blood clotting would be dangerous because of an increased risk of bleeding.

Professor Neil Scolding, from the University of Bristol Institute of Clinical Neurosciences, said: "From the scientific perspective, the exciting thing is that it's pretty much the first time that proteomics has directly yielded a candidate molecule that is both unexpected and novel on the one hand and has therapeutic potential.

"From the clinical perspective, showing that treatment approaches predicted by this proteomic interrogation of MS tissue do have a clear impact in experimental models of MS is extremely promising.

"This points the way to a new area of MS research of considerable interest, and which could well lead in the future to new lines of treatment."

Dr Laura Bell, Research Communications Officer at the MS Society, said she looked forward to seeing how the research progressed.

"This is early research but provides an interesting insight into some of the potential players that cause different types of damage to the central nervous system in people with MS.

"Understanding how MS develops is vital to target therapies for the condition."

http://news.bbc.co.uk/2/hi/health/7247420.stm

Weighty Evidence

Living large can mean dying large, as familiar reminders about obesity's link to cardiovascular disease and diabetes repeatedly emphasize. But those warnings often overshadow another threat from obesity: cancer. Excess weight accounts for 14 percent of cancer deaths in men, and 20 percent in women, researchers estimate. Among all preventable cancer risk factors, only smoking claims more lives.

Obesity's link to cancer should come as no surprise. Signs of that relationship began to emerge 2 decades ago. In the late 1980s, laboratory researchers found connections between cancer and insulin—one of the major hormones that responds to obesity.

While the findings got little attention then, today at least a half-dozen companies are developing cancer drugs that interfere with the hormone's cousin—insulinlike growth factor 1 (IGF-1).
"We've been working on this for 20 years," says Derek LeRoith of the Mount Sinai School of Medicine in New York City. Yet until recently, "nobody ever bought into it." After all, even if a tumor does need insulin, the rest of the body does too. The early research was seen as hardly relevant for disease treatment.

Not so today. If clinical trials find that dampening IGF-1 shrinks tumors in cancer patients, scientists will have not only a new kind of cancer drug but also a new source of insight into the interplay between body weight, metabolism, and cancer. In 2003, a study in the New England Journal of Medicine estimated that if the U.S. population were of a healthier weight, "90,000 deaths due to cancer could be prevented each year." That number may not fall for generations, as obesity rates among even the youngest Americans continue to soar.

Heavy hormones
Lower weight and more physical activity can affect the production of insulin, the hormone that allows the body to soak up fuel. After a meal, food is broken down into glucose, which is the body's main source of energy. Insulin triggers cells to take up and use glucose. As a person gains excess weight, the cells can become resistant to insulin's actions. To compensate, the pancreas begins to produce more insulin, but it can't stay in overdrive indefinitely. Eventually, insulin production will fall and blood glucose levels rise in some people.

The potent hormone IGF-1 and the related IGF-2 are very similar to insulin, helping support rapidly dividing cells, especially during childhood and adolescence. IGF-1 is a powerful driver of cell growth and body size: A toy poodle is a standard poodle with a faulty IGF-1 system.

The link between these insulinlike hormones and obesity is less clear than the connection between insulin and obesity. Although insulin and IGF-1 have individual parking places, or receptors, on a cell, some experiments suggest that at high enough levels, insulin starts to trespass on the IGF-1 receptor, LeRoith says.

In the late 1980s, laboratory researchers demonstrated that IGF-1 might have a role in cancer. Tumor cells were found to contain the IGF-1 receptor. In 1989, experiments with mice showed that blocking the receptor with an antibody could stop tumor growth. Researchers also found that mice bred to lack IGF-1 receptors in all their tissues were born tiny, thereby establishing the hormone's significance in growth. More important for cancer research, cells taken from the miniature mice lacking IGF-1 receptors could not be transformed into tumor cells.

"A cancer cell has to have the IGF-1 receptor," says Renato Baserga of the Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, one of the field's pioneers. "If not, it cannot grow."

At first, results like these were puzzling. Unlike cancer genes that encode other proteins and start down the path to cancer after mutating, the IGF-1 receptor gene wasn't altered in tumors. Also, IGF-1 receptors show up in normal tissues throughout the body. The hormone itself is such a basic substance for animal life that even flies produce it. It was hard to imagine that a normal receptor found in normal cells could have anything to do with cancer.

Then scientists had an idea. Malignant cells may be overly dependent on IGF-1 receptors, on a scale far surpassing the dependence of normal cells. A tumor is like a car—a gas-guzzling Hummer—with a stuck accelerator and no brakes. Even if IGF-1 doesn't spark the ignition, the hormone keeps the gas tank full. Block IGF-1, according to this line of thinking, and the tumor suddenly finds itself running on empty.

Fueling cancer
Still, this notion might have stalled without two other developments. First, epidemiological studies began to find links between cancer and the insulin-IGF axis in people. Then, the entire field of cancer treatment underwent a transformation.

"What got people's attention was the epidemiologic data," says Doug Yee of the University of Minnesota Cancer Center in Minneapolis. In 1998, researchers reported in the journal Science that the risk of prostate cancer among men with the highest circulating levels of IGF-1 was four times as great as the risk among men with the lowest IGF-1 levels. Similar findings quickly followed in breast, colon, and other cancers.

So far, colon cancer has the most consistent association with insulin and IGF-1 levels, says Edward Giovannucci of the Harvard School of Public Health, a coauthor of the 1998 Science study. In 1999, he and his colleagues reported that colon cancer rates were more than twice as high among men who had the highest levels of IGF-1 as they were among men with the lowest IGF-1 levels.

Such findings fit with global patterns of the disease. "If you look at the rates of colon cancer across the world, populations where you expect people to have low insulin invariably have low rates of colon cancer," Giovannucci says. Physical activity and reduced calorie intake can lower insulin levels; populations with more sedentary jobs and calorie-dense diets have higher rates of obesity and higher insulin levels.

"Once you become economically developed, colon cancer rates go up," Giovannucci says. Also, the risks for colon cancer read largely like a list of red flags for type 2 diabetes. Diabetes itself is a risk factor for colon cancer.

Scientists are quick to point out that a higher insulin level isn't the only chemical change that can occur with obesity. Levels of hormones that cause inflammation also rise, as do sex hormones, which can be produced in fat tissue. These and other changes in the body could themselves drive cancer. Or all these fluctuations could work in concert to feed malignancies.

And it might be not only the IGF-1 of middle age that matters, but also the IGF-1 production that orchestrates development early in life. Studies have suggested that babies born at the highest birth weights—and children experiencing early growth spurts—have a greater risk of cancer as adults.

While epidemiologists gathered evidence for a relationship between insulin and cancer, a second, unrelated advance gave the insulin-cancer connection new life: treatment success using antibodies that can attach to precise targets. Antibody-based drugs are large molecules that take the parking space so its rightful owner can't use it. Herceptin, an antibody-based breast cancer treatment, came on the market in 1998, followed by others. Targeted antibodies were suddenly more than theory.

"I think once people got more comfortable making these drugs, the floodgates opened," says Yee. And when pharmaceutical companies started casting for other promising targets for antibody development, the IGF-1 receptor suddenly looked attractive.

"They turned around and said, 'You know, there's this IGF receptor,'" says LeRoith of Mount Sinai. Drug development didn't happen, and perhaps couldn't have, until epidemiology and the technology caught up with the laboratory evidence.

Broad target
Nonetheless, an antibody that interferes with IGF-1 in people raises concerns. Although the full role of IGF-1 in adult tissues is still being worked out, rapidly growing tissues such as those in bone marrow and the intestine might become innocent by-standers of chemotherapy.
"You're going to hit a receptor that's present on every cell in the body, except the liver," LeRoith says.

Also, in a case of molecular friendly fire, the drug might hit unintended targets. Because the insulin receptor and the IGF-1 receptor are cousins—they are actually more than 70 percent alike—some drugmakers worry about the possibility of accidentally interfering with the insulin receptor and making a cancer patient diabetic.

As an endocrinologist, LeRoith isn't as disturbed by these scenarios as some of his colleagues may be. He believes chemotherapy-induced diabetes would be only temporary, and treatable. In the larger picture, it would not be as grave a threat as the cancer itself. Also, he says, chemotherapies already on the market cripple rapidly growing cells in the intestine, bone, and elsewhere. While these drugs do cause notorious side effects, the complications are generally accepted as the price of disease treatment.

So far, though, the experimental drugs haven't caused major problems in early tests. Results of the first human-safety studies are starting to appear, most just in the past few months. The results are encouraging enough that companies are easing into larger studies.

"This was a target that was on everybody's radar screen, but nobody jumped so strongly at it," says Kapil Dhingra of Roche Pharmaceuticals in Nutley, N.J.

They have now. In October, at the International Conference on Molecular Targets and Cancer Therapeutics, researchers from Roche described a study of 34 patients with advanced tumors who received infusions of an experimental drug designed to target the action of IGF-1. Disease in nine patients stabilized. The most common side effects were fatigue, weight loss, and anorexia—complaints that are also often found in patients with advanced cancer. Subjects' blood sugar levels appeared to remain stable.

The trial was designed to test the safety, and not the effectiveness, of the drug. But the researchers noted that it seemed to have a remarkable result in one of the study participants with Ewing's sarcoma, a cancer of children and young adults that Yee in Minnesota had long ago identified as feeding heavily off IGF-1.

"We have a patient, a young woman in her 20s, who really has had honestly one of the best responses I've seen in 20 years," says Razelle Kurzrock of the University of Texas M.D. Anderson Cancer Center in Houston. "When you see something like that in cancer, you've usually hit the molecular target."

Within 6 weeks, the woman's tumor melted away. The results were promising enough that Roche plans to test more patients.

The antibody-based drug that appears to be the farthest along in testing comes from Pfizer Inc., which has moved beyond safety studies into tests that gauge its effectiveness on cancer. Last summer, during a meeting of the American Society of Clinical Oncology, company researchers described results of a trial involving 70 patients with advanced lung cancer. About 46 percent of patients who received the drug in combination with standard chemotherapy improved, compared with 32 percent of those who did not get the anti-IGF-1 drug. Twenty percent of the patients getting the treatment experienced a jump in blood-glucose levels, implying some interaction with insulin. Later this year, the company hopes to report the effects of treatment on patient survival.

Other companies are also working on antitumor antibodies or on smaller molecules that will block the IGF-1 receptor. In the end, researchers say, the drugs may have a role in combination with standard treatments, and trials will probably also find that some tumors are more dependent than others on IGF-1.

"It's not realistic to think that any one target is going to hit all of them," says Kurzrock. Still, she says, "I would say this is going to be a good molecule." If so, a line of research almost lost to the past could one day benefit cancer patients of the future.

http://www.sciencenews.org/articles/20080216/bob9.asp