Cis-diammine dichloroplatinum 11 (CDDP) and alkylating agents are employed in the treatment of a broad spectrum of neoplasms. Thus, efforts to enhance the therapeutic efficacy of these agents are of great clinical importance. This proposal assesses whether cytosine arabinoside (ara-c) synergistically enhances cytoxocity when used in combination with CDDP and nitrogen mustard in human diploid fibroblasts and LoVo colon carcinoma cells. The interaction between ara-c with CDDP and nitrogen mustard is assessed with respect to the inhibition by ara-c of the repair of DNA damage induced by these agents. Whether DNA repair synthesis is inhibited by ara-c and, more specifically, whether this occurs as a result of incorporation of ara-c into DNA undergoing repair after exposure to CDDP and nitrogen mustard are analyzed in this proposal. Also the effect of ara-c on the excision of DNA interstrand cross-links is evaluated. These parameters are then correlated with the enhancement by ara-c of CDDP and nitrogen mustard induced cytotoxicity and assessed for significance. The interaction of these agents is studied in growth-arrested cells as well as proliferating cells. The use of growth-arrested cells permits a clearer analysis of events related to DNA repair. The effect of ara-c is also contrasted with that of aphidicolin, an inhibitor of DNA polymerase alpha that is not incorporated into DNA and the interaction of ara-c and CDDP is contrasted with that of ara-c and trans-diamminedichloroplatinum, an agent that causes fewer DNA interstrand cross-links on an equimolar basis and is less cytotoxic than CDDP. The long term objective is to extend these findings to other alkylating agents and to design more rational clinical trials based on the experimental data.
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