PROTEIN-ASSOCIATED DNA STRAND BREAKS AS INDICATOR OF TOPOI

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The protein-associated DNA single and double-strand breaks induced in mammalian cells by DNA intercalating agents and epipodophyllotoxins have been shown to represent an effect on topoisomerase II. The aim of this project is to investigate the relationship between the drug-induced protein-assoicated strand breaks and the physiological state and pharmacological sensitivity of cells. A correlation was found in V79 cells between protein-associated double-strand breaks and sister-chromaitd exchange, mutation and cytotoxocity. A multi-drug resistant line of Chinese hamster cells exhibited reduced stand break responses to the intercalators, amsacrine and ellipticine, and to the epipodophyllotoxin, etoposide; the uptake of these drugs into the resistant cells was not altered. Protein-associated strand breakage in response to amsacrine and etoposide was found to be dependent upon the proliferation state of NIH 3T3 cells; quiescent cells showed low sensitivity to this responses increased during the onset of DNA synthesis. Further work aims to elucidate the changes in topoisomerase(s) in resistant cells.