The objectives of this grant proposal are: 1) to determine the mechanism by which incorporation of 6-thioguanine into Bacillus subtilis DNA alters the transforming activity of the DNA; 2) to determine the mechanisms of action of selected 9-substituted purines, 9-(n-butyl)-6-thioguanine and 9-ethl-6-mercaptopurine; and 3) to determine the basis for the improved selective toxicity of the 9-substituted purines compared to the purine bases from which they are derived. Objective """"""""1"""""""" relates to the mechanism of action of base analogs which are incorporated into DNA, and furthers the information gained during the previous award interval. Objective """"""""2"""""""" concerns the mechanism(s) of action (currently unknown) of derivatives of the two thiopurines currently in clinical use as antitumor agents. 9-Ethyl-6-mercaptopurine is an active antitumor agent in humans and it and the 9-(n-butyl)-6-thioguanine are active against tumor cells derived for resistance to 6-mercaptopurine and 6-thioguanine. Objective """"""""3"""""""" is an attempt to define the basis for the improved selective toxicity (better chemotherapeutic indexes) for the 9-substituted purines. The methods to be employed include the use of normal cells and transformed human tumor cells in culture and experimental animal tumors in vivo. The long-term goal is to use the information gained to design safer, more effective antitumor agents.
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