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    Research Grants Awarded

    Dietary Glutamine And Protection Against Doxorubicin And Cyclophosphamide Toxicity

    Study Section:
    Treatment

    Scientific Abstract:
    The chemotherapy combination regimens in breast cancer treatment include a combination of doxorubicin (DOX ) and cyclophosphamide (CPA). Each of this chemotherapeutic agents has adverse cardiac effects, that could lead to potentially fatal heart failure. Evidence suggests that DOX- and CPA cardiotoxicity are associated with free radical formation, decreased glutathione and depleted superoxide dismutase in cardiac muscle. Our laboratory found that dietary glutamine (GLN) maintained normal cardiac glutathione (GSH) levels in animals given DOX, CPA or methotrexate (MTX), and prevented lipid peroxidation in the cardiac tissue. Studies on animal models and patients showed that the GLN-reduced MTX toxicity was associated with enhanced tumoricidal effect. Moreover, GLN differentially affected the redox state in normal and cancerous cells in vivo, which could attribute to increased sensitivity of tumor cells to chemotherapy and radiation, while preserving normal tissues. Additionally, GLN down-regulated the anti-apoptotic PI3K/Akt signaling in DMBA-induced breast tumors. The long-term goal of this proposal is to determine if the nutritional conditions could alter the pharmacological response and/or to reduce the side effects of cancer therapy. Our hypothesis is that oral dietary GLN via modulation of GSH synthesis can increase the tumor sensitivity to DOX and CPA, while protecting the heart. We will determine if DOX- and CPA cardiotoxicity is enhanced by a combination therapy and how the proposed protective effect of GLN is affected by combination therapy in the presence of treatable tumor. The specific aims are designed to determine the protective effect of dietary GLN against: 1) DOX- , 2) CPA-, and 3) DOX+CPA heart oxidative damages. Rats with implantable breast cancer will be maintained on GLN diet and given DOX-, CPA- or DOX+CPA injections. Hearts, livers, tumors and blood will be examined for : i)GSH and oxidized glutathione (GSSG) levels; ii)lipid peroxidation; iii)caspase-3 activation and apoptosis/necrosis; iv) peroxidase (GSHPx)-, superoxide dismutases (SOD)- and catalase activity. Cardiac a-actin- and 70KDa heat shock protein (HSP70) mRNA levels will be used as markers for cardiac oxidative damage. Tumor number and weight will be correlated with the results from the above assays. The results of this study could help to develop therapeutic strategies for intensifying chemotherapeutic regimens containing DOX and CPA by preventing their limiting toxicities.

    Lay Abstract:
    Doxorubicin (Dox) and cyclophosphamide (CPA) are anti-cancer agents commonly used in breast cancer treatment. Their clinical use however is limited by the development of life threatening cardiomyopathy. Both anti-cancer agents are often used in combination, which further enhances the possibility of cardiotoxicity. Extensive evidence suggests that doxorubicin- and cyclophosphamide-induced cardiotoxicity occurs through formation of free radicals and depletion of cardiac glutathione (GSH) levels. Our laboratory has previously demonstrated that oral glutamine (GLN) supplementation effectively maintained cardiac glutathione GSH levels in animals given doxorubicin or cylophosphamide. Our data and that of others have also shown that dietary GLN differentially affects the redox state (determined as a ratio GSH/oxidized GSH) in normal and cancerous cells in vivo , which attributes to increased sensitivity of tumor cells to chemotherapy and radiation, while preserving normal tissues. The differential effect of GLN on GSH metabolism in normal and tumorous tissue was accompanied by inhibition of anti-apoptotic PI3K signaling pathway. Our hypothesis is that GLN supplementation through modulation of GSH synthesis increases sensitivity of tumors to DOX and CPA, while protecting the heart. The proposed experiments would determine if DOX- and CPA cardiotoxicity is enhanced by a combination therapy and how the proposed protective effect of GLN is affected by combination therapy in the presence of treatable tumor. The specific aims are designed to determine the protective effect of oral dietary GLN against: 1) doxorubicin- 2) cyclophosphamide-and 3) combination of DOX and CPA-mediated cardiac oxidative damages in implantable breast cancer model of rats. We will examine the effect of GLN on GSH; GSSG; lipid peroxidation; caspase-3 activation and apoptosis/necrosis ; peroxidase (GSHPx)-, superoxide dismutases (SOD)- and catalase activity in heart, liver, tumors and blood, as well as cardiac a-actin- and HSP70 mRNA levels of tumor-bearing rats treated with DOX, CPA or DOX+CPA. The results from the above assays will be correlated with tumor numbers, weight and volumes. The results of this study could help to develop therapeutic strategies for intensifying chemotherapeutic regimens containing doxorubicin and cyclophosphamide by preventing their limiting toxicities.