The proposed research is designed to yield a better understanding of the role of calcium in control of cancer cell proliferation. This study will investigate the importance of calcium in regulating proliferation of specific cancers. Reports have now characterized calcium-dependent growth in malignant cells. We have demonstrated and present in this proposal that certain cancer cells release hypercalcemic factors in vivo and that these cancer cells are growth-sensitive to calcium. Our first hypothesis is that this tumor-induced calcium mobilization cycle can be pharmacologically interrupted by use of calcium antagonists. Our second hypothesis is that cancer cells that induce hypercalcemia and are growth responsive to calcium possess intrinsic and measurable differences in the concentration or binding activity of nitrendipine sensitive calcium slow channels. In vitro evidence has shown that cancers, especially breast cancers, secrete factors that resorb bone calcium. Little is known about the advantage cancers may obtain by inducing hypercalcemia. This study will help elucidate possible mechanisms for cancer cell proliferation involving calcium mobilization and cell calcium metabolism. We will further characterize specific calcium regulating agents such as calcium channel agonists and antagonists for possible therapeutic use in control of malignant cell growth in vivo using nude mice injected with malignant cells and the 7,12 dimethylbenz (a) anthracine (DMBA)-induced rat mammary carcinoma model. The significance of the present study is that is should provide evidence for the importance or lack of importance of calcium antagonists and agonists as regulatory drugs for modifying growth of specific cancers in vivo and in vitro. Hormone and drug sensitivity of normal and neoplastic tissues is to a significant degree related to the concentration of their specific receptors. This observation has been found to be useful in the treatment selection for cancer patients with hormonally responsive tumors. This study will provide evidence for possible clinical utility of measuring tumor nitrendipine receptors for predicting the therapeutic usefulness of calcium antagonists for arrest of tumor growth. Most importantly, the finding that calcium regulating agents can alter cancer cell growth may result in a unique form of cancer chemotherapy and increases the number of tumor types amenable to drug therapy.
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