Current efforts in this laboratory are directed towards the molecular mechanism of action of three classes of anti-cancer agents. The mechanism by which intercalating agents such as adriamycin and actinomycin-D produce strand breaks in DNA is being investigated. We have found both single strand breaks and double strand breaks in mammalian cells following exposure to these drugs and we are attempting to determine what cellular enzyme is responsible for these breaks. We have isolated a topoisomerase which we believe may be responsible for this lesion and we are attempting to characterize this enzyme further. In addition, we are looking for evidence that hexamethylmelamine and pentamethylmelamine act by damaging DNA. We have already shown that single strand breaks and DNA-DNA crosslinks do not result following treatment of mammalian cells with these drugs in cytocidal conditions. We are now looking for evidence of monofunctional adduct formation. Finally, correlation between DNA crosslink formation, DNA synthesis inhibition, and cell cycle traverse perturbations following treatment of mammalian cells with bifunctional alkylating agents is being pursued. We are combining the techniques of alkaline elution, thymidine incorporation, and flow micro-fluorometry to elucidate this problem.
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