Researchers have developed a novel animal model showing that four commonly used chemotherapy drugs disrupt the birth of new brain cells, and that the condition could be partially reversed with the growth factor IGF-1. 

Published early online in the journal Cancer Investigation, the University of Rochester Medical Center study is relevant to the legions of cancer survivors who experience a frustrating decline in cognitive function after chemotherapy treatment, known as chemo-brain. 

“It is not yet clear how our results can be generally applied to humans but we have taken a very significant step toward reproducing a debilitating condition and finding ways to treat it,” said Robert Gross, M.D., Ph.D., professor of Neurology and of Pharmacology and Physiology at URMC and principal investigator of the study. 

Chemo-brain is a newly recognized condition. The URMC team found surprising data about how the four drugs impact the brain, Gross said, and they are the first to report that the experimental insulin-like growth factor, IGF-1, may be beneficial. 

The study was funded by a Department of Defense grant to Gross and by the National Cancer Institute to co-investigator and lead author, Michelle Janelsins, Ph.D., research assistant professor of Radiation Oncology at the James P. Wilmot Cancer Center. 

More than 11 million Americans are living today after receiving a cancer diagnosis. Many of them have endured chemotherapy and although the side effects during treatment are well known, the lingering neurological effects are more puzzling. Patients often report memory lapses, trouble concentrating, confusion, difficulty multi-tasking and slow thinking for weeks, months or years after treatment ends. 

The URMC team hypothesized that cognitive problems might stem from chemo destroying the ability of brain cells to regenerate in the hippocampus, which is primarily involved in memory formation and mood. They sought a way to find the mechanisms at work and to manage the adverse effects on the brain before, during and after chemotherapy treatment. 

Researchers also hypothesized that chemotherapy drugs known to cross the blood-brain barrier would be a bigger threat to brain cells than drugs that do not cross the blood-brain barrier. To test the hypothesis, they investigated the effects of routinely used doses of cyclophosphamide and fluorouracil, which do cross into the brain, against paclitaxel and doxorubicin, which do not. 

Unexpectedly, all four drugs caused a significant breakdown in brain cell proliferation in the animal model. A statistical analysis of cell regeneration showed a 15.4 percent reduction in new brain cells following fluorouracil, a 30.5 percent reduction following cyclophosphamide, a 22.4 percent reduction following doxorubicin, and a 36 percent reduction following paclitaxel. 

“It could be that all of the chemo drugs cross into the brain after all, or that they act via peripheral mechanisms, such as inflammation, that could open up the blood-brain barrier,” Gross said. 

“Neurogenesis can also be altered by stress, sleep deprivation and depression, all of which are common among cancer patients,” added Janelsins. “More thorough studies are needed to understand the interplay of these factors and the long-term effects of chemotherapy on the brain.” 

Researchers conducted a second study of a single high dose of cyclophosphamide, a mainstay of adjuvant chemotherapy for breast cancer, because chemo-brain is a frequent complaint of people receiving this drug. The single high dose resulted in a 40.9 percent reduction in newly divided brain cells, the study said. 

In previous studies the experimental growth hormone IGF-1 had demonstrated that it could generally promote new brain cell development within the central nervous system. Thus, investigators chose to test its effect in the animal model. 

They administered IGF-1 prior to and following a conventional cyclophosphamide multiple-dose regimen, and a single, high-dose of cyclophosphamide. The IGF-1 seemed to increase the number of new brain cells in both models, but was more effective in the high-dose model, the study concluded.

The research team plans to conduct additional studies which will allow them to further test the impact of IGF-1 and other related interventions on the molecular and behavioral consequences of chemotherapy. 

Literature: University of Rochester Medical Center, UR study reveals chemo’s toxicity to brain, possible treatment, December 17, 2009

Study shows deterioration in brain function following breast cancer therapy has negative effects on quality of life

One of the most problematic side effects of cancer treatment, chemobrain – a range of symptoms including memory loss, inability to concentrate, difficulty thinking and other subtle cognitive changes following chemotherapy – seriously diminishes women’s quality of life and daily functioning. As a result, they have to adopt a range of coping strategies to manage their restricted social and professional lives.

Breast cancer survivors tell their story in a descriptive study (1) of the effects that cognitive impairment has on women’s work, social networks and dealings with the health care profession. Dr. Saskia Subramanian from the UCLA Center for Culture and Health in the US and her colleagues have just published their work online in Springer’s Journal of Cancer Survivorship.

An increasing number of women survive breast cancer, yet survival comes at a price. Mild cognitive impairment following chemotherapy, known as “chemobrain” or “chemofog” is one of the most commonly reported post-treatment symptoms by breast cancer survivors. Dr. Subramanian and colleagues’ work shows that this deterioration in brain function has devastating effects on breast cancer survivors’ quality of life.

Through a combination of focus groups and in-depth interviews among 74 women who had completed their course of cancer treatment at least a year earlier, the researchers gathered data on patients’ medical background, treatment experience, post-treatment symptoms, reactions from medical staff and from family and friends, self-management, strength of social networks and their perceptions of themselves.

The women described a variety of cognitive changes which they found both frustrating and upsetting. Some were less able to retain material or to digest new information and recognized that they were not functioning as they once did. Others faced reduced independence, becoming limited in their ability to manage certain responsibilities or get around. These changes made women feel scared, dependent and emotionally drained. For some, coping meant having to cut back on work and social activities. Others had more or less accepted the limitations put on their lives and resigned themselves to a diminished cognitive capacity.

The majority of women complained about the lack of acknowledgement from the medical community when they mentioned their chemobrain symptoms. Many women wished they had received some warning and only a few got answers from their physicians. Some women felt that chemobrain confused their families and friends, and young children in particular.

Chemobrain also affected women’s performance at work. Because they were less able to focus, duties became more difficult and often took longer. This affected their efficiency and reduced their chances of promotion or assignment to projects.

The authors conclude: “These data underscore the very serious ways in which chemobrain can affect the life experiences of cancer survivors – emotionally, psychologically and economically. A clear understanding of the cognitive impairments experienced by survivors will aid researchers in developing targeted therapies and interventions aimed at improving or mitigating these post-treatment side effects.”

Reference:   Boykoff N, Moieni M, Subramanian S (2009). Confronting chemobrain: an in-depth look at survivors’ reports of impact on work, social networks, and health care response. Journal of Cancer Survivorship; DOI: 10.1007/s11764-009-0098-x

As we watched each of our five grandchildren and their friends enter this world and begin their life’s journey, it became more and more clear that something is amiss with this generation.  How are your children and your friend’s children doing?

In the United States, one of three of the children in this generation suffers from a chronic illness.  Perhaps it’s cancer, or birth defects, perhaps asthma, or a problem that affects the child’s mind and behavior, such as Downs Syndrome, learning disorders, ADHD or autism.  Though one in three may sound exaggerated, unbelievable, the figures are there amidst various government files.

This generation is different.  Childhood cancer, once a medical rarity, has grown 67 percent since 1950.  Asthma has increased 140 percent in the last twenty years and autism rates without a doubt have increased at least 200 percent.  Miscarriages and premature births are also on the rise, while the ratio of male babies dwindles and girls face endometriosis even in teenage.

The generations born from 1970 on are the first to be raised in a truly toxified world.  Even before conception and on into adulthood, the assault is everywhere: heavy metals and carcinogenic particles in air pollution; industrial solvents, household detergents, prozac and radioactive wastes in drinking water; pesticides in flea collars; artificial growth hormones in beef, arsenic in chicken; synthetic hormones in bottles, teething rings and medical devices; formaldehyde in cribs and nail polish, and even rocket fuel in lettuce.   Pacifiers are now manufactured with nanoparticles from silver, to be sold as “antibacterial.”  What’s wrong with rinsing a pacifier in soapy water?

Despite naysayers (who pays them to say nay? ”that’s a whole story in itself), it’s clear there is both an association and a causative connection between the vast explosion of poisons in our everyday lives and our children’s “issues.”  Over 80,000 industrial chemicals (tested only by the manufacturer) are in commerce in this country, produced or imported at 15 trillion pounds a year.   Pesticide use has leapt from the troubling 400 million pounds Rachel Carson wrote about in the 1960s to the mind-boggling 4.4 billion pounds in use today.   Nuclear power plants, aging and under-maintained, increasingly leak wastes, often without notifying their community.

What could be more elemental than our desire to protect our children.  Children and fetuses, because of their undeveloped defense systems, are ten to sixty-five times more susceptible to specific toxics than adults.  These toxics diminish the capacities of our children…the future of our families, our communities, our nation, and yours.

Illness does not necessarily show up in childhood.  Environmental exposures, from conception to early life, can set a person´s cellular code for life and can cause disease at any time, through old age. This accounts for the rise in Parkinson´s and Alzheimer´s diseases, prostate and breast cancer.

Yet this is not the dispiriting “Bad News” it might seem.  It is, actually, a message of hope and optimism.  We are fearful only when we are ignorant and powerless.  Now that we know what is happening, we can determine not to let it happen further.

These poisons are manmade; manufacturers can take them out of our children´s lives and make profits from safe products.  “Green chemistry” can replace toxic molecules with harmless ones.  We can connect global climate change actions to environmental health strategies.  If we replace coal-fired power, in the process we reduce not only carbon but also emissions of the tons of lead, mercury, hydrochloric acid, chromium, arsenic, sulfur and nitrogen oxides that cause autism, Alzheimer’s and other public health menaces.

We cannot bury our heads and hope it will all go away.  We cannot leave the job to someone else.  Some may feel the problem is so massive, it’s best to pretend it doesn’t exist.  But it isn’t more massive than we allow it to be.  It’s totally within our reach.

Here America, we look to Europe for ideas and strategies you have used, for the research coming out of your universities, for an understanding of the politics that enable your governments to pass strong environmental health laws.  The weed killer named atrazine in the U.S., made by Syngenta, a Swiss company, has never been approved for use in Europe.  But in the U.S., it is used on tens of millions of acres of farmland, on our lawns, gardens, parks, and golf courses.   Why?  And why has Europe begun screening chemicals under the REACH program, while industry in the U.S. has successfully opposed it?

Learning from each other, we can make each other smarter and stronger.  It is in our power to learn about what harms our children, to share our knowledge, and to demand action.

Author: Alice Shabecoff for CSN – Chemical Sensitivity Network, September 14, 2009

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Alice Shabecoff is the co-author with her husband Philip of Poisoned Profits: The Toxic Assault on our Children, published by Random House last year.  See their website, www.poisonedprofits.com.

Research by UC Riverside scientists is first to link passive smoking to nonalcoholic fatty liver disease

A team of scientists at the University of California, Riverside has found that even second-hand tobacco smoke exposure can result in nonalcoholic fatty liver disease (NAFLD), a common disease and rising cause of chronic liver injury in which fat accumulates in the liver of people who drink little or no alcohol. 

The researchers found fat accumulated in liver cells of mice exposed to second-hand cigarette smoke for a year in the lab. Such fat buildup is a sign of NAFLD, leading eventually to liver dysfunction. 

In their study, the researchers focused on two key regulators of lipid (fat) metabolism that are found in many human cells as well: SREBP (sterol regulatory element-binding protein) that stimulates synthesis of fatty acids in the liver, and AMPK (adenosine monophosphate kinase) that turns SREBP on and off. 

They found that second-hand smoke exposure inhibits AMPK activity, which, in turn, causes an increase in activity of SREBP. When SREBP is more active, more fatty acids get synthesized. The result is NAFLD induced by second-hand smoke. 

“Our study provides compelling experimental evidence in support of tobacco smoke exposure playing a major role in NAFLD development,” said Manuela Martins-Green, a professor of cell biology, who led the study. “Our work points to SREBP and AMPK as new molecular targets for drug therapy that can reverse NAFLD development resulting from second-hand smoke. Drugs could now be developed that stimulate AMPK activity, and thereby inhibit SREBP, leading to reduced fatty acid production in the liver.” 

Results of the study appear in the September issue of the Journal of Hepatology. 

The study emphasizes that discouraging cigarette smoking helps prevent not only cardiovascular disease, pulmonary disease and cancer, but now also liver disease. 

Second-hand smoke is the combination of smoke exhaled by a smoker and smoke given off by the burning end of a tobacco product. Lingering in the air long after tobacco products have been extinguished, it is involuntarily inhaled by nonsmokers in the vicinity. 

Second-hand smoke is a major toxicant that affects children, the elderly and nonsmokers living in the household of adults who smoke. Many state and local governments have passed laws prohibiting smoking in public facilities. Diseases associated with second-hand smoking include cancer, heart disease, atherosclerosis, pneumonia, bronchitis and severe asthma. 

Despite the large body of scientific evidence documenting the effects of passive or active smoking on the heart and lungs, reports investigating how smoking causes liver injury are scant. 

“Until our study, second-hand smoking had not been linked to NAFLD development,” Martins-Green said. 

She was joined in the study by her graduate student Hongwei Yuan (first author of the research paper and now a postdoctoral researcher in her lab) and UC Riverside’s John Shyy, a professor of biomedical sciences. Next, the team plans to investigate the clinical relevance of their findings. A grant to Martins-Green from Philip Morris USA, Inc., supported the research. 

Reference: University of California, Second-hand smoking results in liver disease, study finds, RIVERSIDE, Calif., September 10, 2009

Picture: Martins-Green lab, UC Riverside

Scientists here are the first to demonstrate that the link between diesel fume exposure and cancer lies in the ability of diesel exhaust to induce the growth of new blood vessels that serve as a food supply for solid tumors. 

The researchers found that in both healthy and diseased animals, more new blood vessels sprouted in mice exposed to diesel exhaust than did in mice exposed to clean, filtered air. This suggests that previous illness isn’t required to make humans susceptible to the damaging effects of the diesel exhaust. 

The tiny size of inhaled diesel particles, most less than 0.1 microns in diameter, potentially enables them to penetrate the human circulatory system, organs and tissues, meaning they can do this damage just about anywhere in the body. A micron is one millionth of a meter. 

Diesel exhaust exposure levels in the study were designed to mimic the exposure people might experience while living in urban areas and commuting in heavy traffic. The levels were lower than or similar to those typically experienced by workers who use diesel-powered equipment, who tend to work in mines, on bridges and tunnels, along railroads, at loading docks, on farms and in vehicle maintenance garages, according to the U.S. Department of Labor. 

“The message from our study is that exposure to diesel exhaust for just a short time period of two months could give even normal tissue the potential to develop a tumor,” said Qinghua Sun, senior author of the study and an assistant professor of environmental health sciences at Ohio State University. 

“We need to raise public awareness so people give more thought to how they drive and how they live so they can pursue ways to protect themselves and improve their health. And we still have a lot of work to do to improve diesel engines so they generate fewer particles and exhaust that can be released into the ambient air.”

The research appears online and is scheduled for later print publication in the journal Toxicology Letters. 

The researchers experimented with mice that resembled two conditions that could be present in a human body. In one, the scientists implanted a small platform seeded with normal endothelial cells, the cells that line blood vessels, under the skin of the mice. This was designed to mimic relatively normal conditions in human bodies for cell growth. 

In the other, the researchers created an environment that would follow a significant loss of blood flow to a section of a vessel, called ischemia, in the hind limbs of the mice. This generated severe hypoxia, an area with low or no oxygen, a condition that is present in certain diseases. 

Both types of mice were then exposed to either whole diesel exhaust containing particles at a concentration of about 1 milligram per cubic meter, or to filtered outdoor air, for six hours per day five days a week. The rest of the time they breathed filtered air in their cages. Effects of the exposure were measured after two weeks, five weeks and eight weeks of the exposures.  

Though some blood vessel growth and chemical changes could be seen in the mice after two weeks of exposure, “generally, the longer the exposure, the more effects we could see,” said Sun, also an investigator in Ohio State’s Davis Heart and Lung Research Institute. “It’s difficult to translate outcomes from an animal study directly to the human experience, but the bottom line is, the shorter the exposure to diesel exhaust, the better.” 

The exposure to diesel exhaust caused a six-fold increase in new blood vessel formation in the ischemic hind limbs after eight weeks and a four-fold increase in vessel sprouting in the normal hind limbs of the mice in the same amount of time, compared to mice breathing filtered air.  

The researchers also saw significantly more blood vessel growth in the implanted cells and in rings of tissue taken from the aortas of mice exposed to the exhaust compared to the control mice exposed to clean air. In fact, the researchers found that three types of blood vessel development occurred in these areas after exposure to the diesel exhaust: angiogenesis, the development of new capillaries; arteriogenesis, the maturation or re-started growth of existing vessels; and vasculogenesis, the formation of new blood vessels. 

All of these processes are associated with tumor growth, but unprogrammed angiogenesis in particular can wreak havoc in the human body, Sun said. 

“Whenever you talk about a solid tumor, angiogenesis is one of the fundamental mechanisms behind its development. Angiogenesis provides the means for tumor cells to grow because they have to have a blood supply. Without a blood supply, solid tumors will not grow,” he said. 

“We want our bodies to generate new blood vessels only when we need them. And then stop producing them when we need them to stop.” 

Though the researchers have not defined every mechanism behind these processes, they sought to explain at least a few ways in which blood vessels are able to sprout or mature after exposure to diesel exhaust.  

They observed that diesel exhaust exposure activated a chemical signal, vascular endothelial growth factor, which has long been associated with new blood vessel development. The exposure also increased levels of a protein, hypoxia-inducible factor 1, that is essential to blood vessel development when oxygen levels are low. At the same time, the presence of the exhaust lowered the activity of an enzyme that has a role in producing substances that can suppress tumor growth. 

The scientists also tracked low-grade inflammation in tissues exposed to the exhaust, which is often associated with tumor development. 

Though the tiny size of diesel exhaust particles may contribute to their ability to penetrate all areas of the body, Sun noted that their complex chemical composition, and the way in which those chemicals are released once particles enter the body, also influence how they react with human cells.  

Gasoline exhaust particles are larger than diesel fume particles, but it’s premature to suggest that they are any less dangerous to humans, Sun said. 

“The bigger particles are known to be harmful primarily for upper respiratory tract illnesses. Larger particles also can’t travel long distances – they tend to fall to the ground,” he said. “Smaller particles hover in the air for a long time and can have long-term impact on humans when inhaled.”

Sun and colleagues are now conducting a study testing whether the exhaust particles promote tumor development and metastasis. 

This work is supported by Health Effects Institute awards and grants from the National Institutes of Health.  

Reference:    Ohio State University, Diesel Exhaust is linked to Cancer Developement via new Blood Vessel Growth, Columbus, Ohio, September 2, 2009