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    Research Grants Awarded

    Adverse neurological consequences of breast cancer treatments: Causes and prevention

    Study Section:
    Psychosocial and Complementary Treatment Approache

    Scientific Abstract:
    One of the central goals of cancer research is to develop means of killing cancer cells in a manner that does not further compromise the health of individuals with cancer. In the case of breast cancer, there are increasing indications that some of the important, but poorly studied, consequences of treatment with chemotherapy involve damage to the CNS, with various studies suggesting some degree of cognitive impairment in 18% of individuals treated systemically for low-grade tumors, 30% of individuals receiving high-does chemotherapy, and with delayed neurological changes in up to 70% of individuals. The biological basis for these effects is poorly understood. Equally unknown are the reasons why some individuals are more severely affected than others, as well as means by which such damage can be prevented without compromising tumor elimination. This research effort is based on findings that tamoxifen (TMX) and 5-fluorouracil (5-FU) are toxic for the normal progenitor cells and oligodendrocytes of the brain at clinically relevant exposure levels in vitro and in vivo. Our preliminary observations also demonstrate that systemic exposure to 5-FU causes delayed damage in the CNS, as has been observed in breast cancer patients treated with systemic chemotherapy, thus providing the first animal model for such delayed neurological damage. We also provide preliminary observations of strain dependence of the severity of such adverse effects, a potential physiological basis for such differences, and strategies for selectively protecting against such effects during treatment. Our goals in this research application are to advance these studies to (i) more fully define the cellular targets of TMX and 5-FU toxicity in the CNS, (ii) test the hypothesis that analysis of oxidative status can be used to prospectively identify individuals at greater risk for such side effects, and (iii) test the hypothesis that such side-effects to the CNS can be prevented by systemic modification of oxidative status.

    Lay Abstract:
    One of the greatest challenges in cancer treatment is to develop means of killing cancer cells without also damaging the normal cells of the body. Among the troublesome side effects of cancer treatment is damage to the central nervous system (CNS), and studies on individuals with breast cancer have indicated that a significant proportion of such individuals may develop neurological complications, including cognitive impairment, as a consequence of treatment. Little is known about the basis for such damage, and studies in this proposal address this lack of knowledge in several ways. First, we have discovered a striking vulnerability of cells of the brain to two chemotherapeutic agents widely used to treat breast cancer. Systemic administration of tamoxifen or 5-fluoruracil causes increased cell death and reduced cell division in the normal brain. Moreover, 5-fluoruracil also causes a delayed damage to the cells that make the insulating myelin that wraps nerve cells of the CNS and that are essential for normal neuronal function. These findings provide the first animal model for analyzing the appearance of damage to the CNS months after completion of treatment. We also have identified strains of mice that differ in the degree of their vulnerability, and provide data that the key difference between the cells of these animals may be a definable physiological parameter that may enable advance identification of individuals at greater risk for suffering adverse effects of chemotherapy. Finally, our studies also studies suggest means by which these adverse effects can be prevented without compromising killing of cancer cells themselves