Treatment of malignant gliomas of the central nervous system is unsuccessful despite current multimodality approaches. Therefor, new targets for drug development are warranted. We have concentrated on second messenger systems in normal and malignant tissues and have focused recently on the calcium/calmodulin (CaM) cascade of signal transduction in malignant brain tissues. We have found that drugs that bind to and inhibit the function of CaM are effective inhibitors of malignant cell growth in vitro and in vivo and have characterized new and promising derivatives. Our studies revealed the identity of CaM from gliomas and normal brain and now turn our attention to CaM binding proteins. In the current proposal we plan to continue the above investigations plus characterize the targets for CaM in normal and malignant brain tissues. In particular, we will focus on CaM kinases since they represent a major component of this signal transduction cascade, and since we have already found marked differences in the enzyme in certain glioma lines. By characterizing these enzymes in detail, we propose means by which to inhibit their activity and testing the effect of inhibition of enzymic activity on the growth of human glioma xenografts. In addition we have found that the addition of CaM antagonists to bleomycin produced synergistic cell kill in certain sensitive lines, including C6 astrocytoma. During this renewal period we will extend these studies to include testing of liblomycin, a lipophilic synthetic derivative which lacks pulmonary toxicity and has more favorable pharmacodynamics. Through a clearer understanding of the mechanism by which anti-CaMs augment bleomycin cytotoxicity, we might be able to identify promising new approaches to these fatal malignancies.
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