The radiation sensitizer Misonidazole (MISO) can selectively potentiate the effectiveness of certain conventional chemotherapeutic agents in vitro and in vivo. In virtually every system tested, the enhancement of tumor toxicity has exceeded any concommitant increase in normal tissue damage. In order to accurately evaluate the potential of this therapy and to exploit it to the fullest, it is necessary to establish underlying mechanisms. One long term objective of this proposal is to examine the mechanisms of chemopotentiation when cells are incubated with MISO after treatment with nitrosoureas. The extent and kinetics of DNA cross-link formation after treatment will be assessed in EMT-6 cells and two human cell lines, IMR-90 and VA-13. The latter cell line is deficient (Mer-) in alklytransferase activity and inefficient at excising chloroethyl monoadducts from DNA after nitrosourea treatment, while the former demonstrates this ability (Mer+). The role of alkyltransferase activity in chemopotentiation by MISO will be examined. Glutathione (GSH) depletion will also be monitored. Both effects will be compared to the magnitude of chemopotentiation and the loss of chemopotentiation when post-incubation with MISO is delayed after nitrosourea treatment. The second long term objective of the proposed research is to synthesize improved chemopotentiating agents based on our previous structure-activity investigations. Specifically, experiments will be designed to test the hypothesis that the addition of a side chain, capable of generating an isocyanate, to a nitrogen heterocycle can improve chemopotentiating activity. In preliminary experiments this approach has proven very promising. Synthetic efforts will attempt to define specific structural parameters influencing the chemosensitizing, radiosensitizing, and cytotoxic properties of isocyanate-generating nitroheterocyles in vitro and in vivo.
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