The long range objective of this research project is to provide a rational basis for the design of new CC-1065 analogs with improved chemotherapeutic potential as antitumor agents. Collaborative studies carried out concurrently at Austin (UT) and Kalamazoo (Upjohn) have provided structural information on the CC-1065-DNA adduct as well as insight into the biochemical response to the DNA damage produced by CC-1065. Taken together these results suggest three alternative ways in which CC-1065 may exert its considerable potency as an antitumor agent. During the next project period, we propose to pin-point the molecular basis for the antitumor activity of CC-1065. Our strategy will involve correlation of biological (antitumor) and biochemical activities with structural alterations in the CC-1065-analog-DNA adducts. The three dimensional structural characterization of the CC-1065-DNA adduct and analog complexes will rely upon 1H-NMR (and possibly X-ray crystallographic analysis) studies on the defined CC-1065-oligodeoxyduplex adduct. Biochemical parameters monitored in response to CC-1065-DNA damage include DNA sequence specificity, tele-stability effects, DNA repair consequences and possibly the effects of CC-1065 on gene expression using SV40 DNA. The synthesis of CC-1065 analogs, and their biological evaluation for antitumor activity and toxicity will be conducted in a separate effort funded by The Upjohn Company. The results of this investigation will not only provide a rational basis for the design of new CC-1065 analogs with improved chemotherapeutic properties, but will provide considerable insight into the mechanisms whereby specific chemical modifications of DNA effect its structure and function.
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