EFFECT OF CALMODULIN INHIBITORS ON ADRIAMYCIN RESISTANCE

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The overall objective of this proposal is to evaluate the effect of calmodulin inhibitors in vivo, on the antitumor activity of adriamycin in progressively resistant cells and the toxicity of adriamycin to normal susceptible target tissues. These studies will be important to expand our understanding of the mechanisms of resistance and ultimately in the design of chemotherapeutic strategies for the management of tumors resistant to anthracycline chemotherapy. The tumor systems to be used in this study will include the parent-sensitive and progressively adriamycin-resistant variants of the P388 and L1210 mouse leukemia and the B16-BL6 mouse melanoma. The calmodulin inhibitors to be evaluated are N-(4-aminobutyl)-5-chloro-2-naphtalenesulfonamide (W-13), trifluoperazine, prochlorperazine and chlorpromazine. The sensitve and progressively resistant tumors for in vivo antitumor studies will be initially characterized to determine the effect of calmodulin inhibitors on the accumulation, retention, and cytotoxic effects of adriamycin. Cellular adriamycin levels will be measured by fluorometry and also by laser flow cytometry to determine heterogeneity in the cellular distribution of adriamycin fluorescence. Drug-induced cytotoxic effects will be based on the colony-forming ability of the treated tumor cells in soft agar. Proliferative changes in the tumor cells will be determined by measuring the uptake of 3H-thymidine and the determination of perturbations in cell cycle traverse by flow cytometry. Antitumor effects in vivo will be determined by measuring changes in tumor volume and the prolongation in life-span of treated animals. Possible exacerbation in adriamycin-induced toxicity in vivo to normal target tissues due to the calmodulin inhibitors will be based on evaluating proliferation and damage in duodenal crypt and bone marrow cells and by quantitating myocardial damage.