Camptothecins are a very promising group of strong topoisomerase I poisons that have shown good activity against a variety of human cancers in clinical trials. Several key contributions to our understanding of the cytotoxic mechanisms of camptothecins have been made with studies of simian virus 40 (SV40), a small double strand DNA virus which makes such extensive use of host cell chromosomal proteins and enzymes of DNA replication and transcription that it is considered a """"""""minichromosome"""""""" and model for the mammalian replicon. As a model system, SV40 has unique advantages and has made many contributions to our understanding of mammalian DNA replication and transcription. The hypothesis of this proposed study is that our understanding of the molecular biology of camptothecin action can be significantly advanced by two developments of the SV40 model system: (1) the study of camptothecin-resistant mutants of CV-1 host cells for SV40 infections and (2) studies using mutants of SV40 with greatly increased infectivity for human cells. The primary goal of the studies is to understand the structure and processing of camptothecin-induced DNA lesions and how these can be modulated by other treatments. The unique advantages of the SV40 system will allow us to analyze disruptions in DNA replication and transcription in unusual molecular detail. Secondary goals include complete characterization of the camptothecin resistant CV-1 cell mutants, studies of camptothecin effects on DNA replication in human genetic instability syndromes hypersensitive to camptothecins and understanding of the roles of topoisomerases I and IIbeta in transcription. The rational for the studies is that improved understanding of camptothecin-induced damage and its processing will provide valuable information for the design of new drugs of this class and for new treatment combinations.
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