DNA Repair Characteristics of Walker Rat Carcinoma Cells Sensitive and Resistant to Cis-Diamminedichloroplatinum(II) (Cisplatin) and Difunctional Alkylating Agents
Studies on cultured cells have indicated the likely relevance of platinum DNA binding to cytotoxicity following their treatment with cis-diamminedichloroplatinum(II) (cisplatin) (1,2). DNA has been shown to be the only macromolecular target that is large enough to undergo more than one hit per molecule at pharmacologically relevant doses (1). Current evidence favours the view that damage to DNA leads to the inhibition of DNA synthesis and this in turn leads to cell death probably as a consequence of associated chromosomal damage. Cisplatin and di-functional alkylating agents can react with DNA to form both inter- and intra-strand crosslinks, crosslinks between DNA and protein and mono-functional adducts. A correlation between interstrand crosslinking and cytotoxicity has been demonstrated in the case of cis and trans diamminedichloroplatinum(II)-treated Hela (3) Chinese hamster (4) and mouse cells (5,6). Again, investigations in mouse leukaemia cells and normal and transformed human cells of varying sensitivity to cisplatin have shown that sensitivity often correlates well with interstrand crosslink formation (7,8,9). No similar correlation has been found for DNA-protein crosslinking and cytotoxicity in Chinese hamster (4) or mouse cells (6). In order to assess the possible importance of DNA crosslink formation we have studied the DNA excision repair characteristics of two lines of Walker rat cells sensitive and resistant to cisplatin and difunctional cytotoxic agents but not to monofunctional, cytotoxic agents. Additionally we have examined the biochemical responses of the two cell lines to DNA damage.
KeywordsSulphur Mustard Leukemia L1210 Cell Interstrand Crosslinking Murine Leukemia L1210 Cell L1210 Mouse Leukemia Cell
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