Nerve Protecting Agents May Help Prevent Chemotherapy-Induced Anemia

Main Category: Cancer / Oncology
Also Included In: Neurology / Neuroscience;??Blood / Hematology
Article Date: 08 May 2013 - 0:00 PDT Current ratings for:
Nerve Protecting Agents May Help Prevent Chemotherapy-Induced Anemia

Cancer chemotherapy can cause peripheral neuropathy - nerve damage often resulting in pain and muscle weakness in the arms and legs. Now, researchers at Albert Einstein College of Medicine of Yeshiva University have discovered that chemo also induces an insidious type of nerve damage inside bone marrow that can cause delays in recovery after bone marrow transplantation. The findings, made in mice and published online in Nature Medicine, suggest that combining chemotherapy with nerve-protecting agents may prevent long-term bone marrow injury that causes anemia and may improve the success of bone marrow transplants.

Constantly regenerating and maturing, the hematopoietic (blood-producing) stem cells in our bone marrow produce billions of red blood cells (RBC) every day. Cancer chemotherapy is notorious for injuring the bone marrow, leading to anemia, or low RBC counts. But just how chemotherapy harms the bone marrow has not been clear.

Anemia can lead to numerous health problems including chronic fatigue, tachycardia (abnormally rapid heartbeat), cognitive impairment, shortness of breath, depression and dizziness. In addition, studies have shown that cancer patients who develop anemia have a 65 percent increased risk of death compared with cancer patients without anemia.

In an earlier study, senior author Paul Frenette, M.D., professor of medicine and of cell biology and director of the Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research at Einstein, found that sympathetic nerves within bone marrow direct the movement of hematopoietic stem cells. (The body's sympathetic nervous system helps in controlling most internal organs - increasing heart rate and dilating the pupils of the eye, for example.)

"Since many chemotherapies used in cancer treatment are neurotoxic, we wondered whether they might also damage sympathetic nerves in bone marrow itself, impairing the ability of hematopoietic cells to regenerate and to manufacture RBCs," said Dr. Frenette. "This possibility hadn't been examined before."

Dr. Frenette and his colleagues treated mice with seven cycles of cisplatin, a common chemotherapy drug with known neurotoxic effects. The cisplatin caused peripheral neuropathy problems similar to those seen in cancer patients. The mice were then given fresh bone marrow transplants to see how well their marrow would regenerate. Despite receiving fresh stem cells, the cisplatin-treated mice had delayed recovery of blood counts compared to controls - suggesting that the prior cisplatin treatments had affected the bone marrow and prevented hematopoietic stem cells from regenerating. By contrast, mice treated with carboplatin - a non-neurotoxic chemotherapy - recovered their ability to produce blood after bone marrow transplantation.

To confirm that healthy sympathetic nerves in the bone marrow are needed to regenerate hematopoietic stem cells and produce RBCs, the researchers selectively damaged sympathetic nerves in bone marrow using chemicals or genetic engineering. In both cases, the mice with the damaged sympathetic nerves were less able than control mice to recover after bone marrow transplant.

The researchers found that injury to these nerves could be reduced by giving mice nerve-protecting agents along with chemotherapy. Mice treated with seven cycles of cisplatin along with 4-methylcatechol (an experimental drug that reportedly protects sympathetic nerves) showed improved response to bone marrow transplantation, compared to controls.

Dr. Frenette and his colleagues now plan to look for compounds that can protect sympathetic nerves in the bone marrow without reducing the effectiveness of cancer chemotherapies.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cancer / oncology section for the latest news on this subject. The title of the paper is "Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration." The lead author of the paper is Daniel Lucas, Ph.D., a postdoctoral reseacher in Dr. Frenette's laboratory. Other Einstein contributors are Christoph Scheiermann, Ph.D., and Yuya Kunisaki, M.D., Ph.D. Additional co-authors are Andrew Chow, M.D./Ph.D. student, Icahn School of Medicine at Mount Sinai, New York, NY; Ingmar Bruns, M.D., Ph.D., Einstein and Heinrich Heine University, Dusseldorf, Germany; Colleen Barrick, National Cancer Institute, Frederick, MD; and Lino Tessarollo, Ph.D., National Cancer Institute.

This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DK056638) and the National Heart, Lung, and Blood Institute (HL069438), both parts of the National Institutes of Health.

A patent application on this technology has been filed, which is currently available for licensing and further commercialization.

The authors declare no competing financial interests.

Albert Einstein College of Medicine

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How Nerve Wiring Self-Destructs Has Relevance To Diseases Of Peripheral And Central Nervous Systems

Main Category: Neurology / Neuroscience
Also Included In: Lymphoma / Leukemia / Myeloma;??Cancer / Oncology
Article Date: 13 May 2013 - 0:00 PDT Current ratings for:
How Nerve Wiring Self-Destructs Has Relevance To Diseases Of Peripheral And Central Nervous Systems

Many medical issues affect nerves, from injuries in car accidents and side effects of chemotherapy to glaucoma and multiple sclerosis. The common theme in these scenarios is destruction of nerve axons, the long wires that transmit signals to other parts of the body, allowing movement, sight and sense of touch, among other vital functions.

Now, researchers at Washington University School of Medicine in St. Louis have found a way the body can remove injured axons, identifying a potential target for new drugs that could prevent the inappropriate loss of axons and maintain nerve function.

"Treating axonal degeneration could potentially help a lot of patients because there are so many diseases and conditions where axons are inappropriately lost," says Aaron DiAntonio, MD, PhD, professor of developmental biology. "While this would not be a cure for any of them, the hope is that we could slow the progression of a whole range of diseases by keeping axons healthy."

DiAntonio is senior author of the study that appears online in the journal Cell Reports.

While axonal degeneration appears to be a major culprit in diseases like multiple sclerosis, it also paradoxically plays an important role in properly wiring the nervous systems of developing embryos.

"When an embryo is building its nervous system, there can be inappropriate or excessive axonal sprouts, or axons that are only needed at one time in development and not later," DiAntonio says. "These axons degenerate, and that's very important for wiring the nervous system. And in adult organisms, it might be useful to have a clean and quick way to remove a damaged axon from a healthy nerve, instead of letting it decay and potentially damage its neighboring axons."

DiAntonio compares the process to programmed cell death, or apoptosis, which is also important in embryonic development. Apoptosis culls unnecessary or damaged cells from the body. If cell death programs become overactive, they can kill healthy cells that should remain. And if apoptosis fails to destroy damaged cells in adults, it can lead to cancer.

The new discovery also underscores the relatively recent understanding that loss of axons is not a passive decay process resulting from injury. Just as apoptosis actively destroys cells, axonal degeneration results from a cellular program that actively removes the damaged axon. In certain diseases, the program may be inappropriately triggered.

"We want to understand axonal degeneration at the same level that we understand programmed cell death, in the hopes of developing drugs to block the process when it becomes overactive," DiAntonio says.

DiAntonio's major collaborators in this project include Jeffrey D. Milbrandt, MD, PhD, the James S. McDonnell Professor and head of the Department of Genetics, and first author Elisabetta Babetto, PhD, postdoctoral research scholar.

Studying mice, the researchers found that a gene called Phr1 plays a major role in governing the self-destruction of injured axons. When they removed Phr1 from adult mice, the severed portion of the axons remained intact for much longer than in genetically normal mice.

In the normal mice, a severed axon degenerated entirely after two days. In mice without Phr1, they found that about 75 percent of the severed axons remained at five days, with a quarter persisting at least 10 days after being cut. The mice showed no side effects and suffered no obvious problems due to the missing Phr1.

The findings raise the possibility that blocking the Phr1 protein with a drug could keep damaged axons alive and functional when the body would normally cause the axons to self-destruct.

DiAntonio emphasizes that he is not trying to save axons that have no connection to the rest of the nerve. The paradigm is simply a good way to model nerve injury. In many instances, such as a crush injury or disease processes in which the axon is not severed, blocking the Phr1 protein could potentially preserve an attached axon that would otherwise self-destruct.

Importantly, the research team also looked at optic nerves of the central nervous system, which are damaged in glaucoma, and found similar protective effects from the loss of Phr1.

"This is not the first gene identified whose loss protects mammalian axons from degeneration," DiAntonio says. "But it is the first one that shows evidence of working in the central nervous system. So it could be important in conditions like glaucoma, multiple sclerosis and other neurodegenerative diseases where the central nervous system is the primary problem."

DiAntonio also points out possible ways to help cancer patients. Many chemotherapy drugs cause damage to peripheral axons, which may limit the doses a patient can tolerate.

As part of the new study, the researchers showed that intact axons without Phr1 were protected from the damage caused by vincristine, a chemotherapy drug used to treat leukemia, neuroblastoma, Hodgkin's disease and non-Hodgkin's lymphoma, among other cancers.

"In this case, the loss of axons is not caused by disease," DiAntonio says. "It's caused by the drug doctors are giving. You know the date it will start. You know the date it will stop. This is probably where I am most optimistic that we could make an impact."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our neurology / neuroscience section for the latest news on this subject. This work was supported by the American-Italian Cancer Foundation, the European Molecular Biology Organization, the Muscular Dystrophy Association and the National Institutes of Health (NIH) grant numbers DA020812, NS065053 and NS078007.
Babetto E, Beirowski B, Russler EV, Milbrandt J, DiAntonio A. The Phr1 ubiquitin ligase promotes injury-induced axon self-destruction. Cell Reports. May 9, 2013.
Washington University School of Medicine Please use one of the following formats to cite this article in your essay, paper or report:

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Predicting Nerve Damage from Paclitaxel

The chemotherapy drug paclitaxel can cause nerve damage in some patients. According to a study that will be presented at the 2011 annual meeting of the American Society of Clinical Oncology, specific genetic markers may eventually allow doctors to know in advance which patients are most likely to experience this side effect.?

Peripheral neuropathy—a condition that can cause pain, burning, tingling, or numbness in the hands and feet—is a potential side effect of taxane chemotherapy drugs such as paclitaxel. The condition can become severe, and may limit the amount of chemotherapy that a patient can receive. ?

To explore the possibility that specific genetic markers may be linked with the development of peripheral neuropathy, researchers collected information about more than 2,000 women who were participating in a breast cancer clinical trial. All the patients received paclitaxel.?

Genetic differences between women who did and did not develop peripheral neuropathy were identified through a process known as a genome-wide association study (GWAS). The researchers scanned complete sets of DNA for small genetic variations known as single-nucleotide polymorphisms (SNPs). ?

Several SNPs were linked with the likelihood of peripheral neuropathy. Results for one of these SNPs, for example, indicated that risk of neuropathy was 27% among patients without the genetic variation (no SNP), 40% among patients with one SNP, and 60% among patients with two SNPs. Neuropathy was also more common in older patients and in African Americans. ?

In a prepared statement, the lead author of the study noted “If these findings can be replicated, this may allow physicians to know prior to recommending therapy?

whether the patient is at an inordinate risk for developing taxane-induced neuropathy. This may allow for better counseling, use of alternative drugs or schedules, or omission of taxanes in the appropriate settings. These genetic findings might also provide insight into the mechanism of this side effect and help develop drugs to prevent this toxicity altogether.”?

Reference: Schneider BP, Li L, Miller K et al. Genetic associations with taxane-induced neuropathy by genome wide association study (GWAS) in E5103. Paper presented at: 2011 Annual Meeting of the American Society of Clinical Oncology; June 3-7, 2011; Chicago, IL. Abstract 1000.?

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