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The Role of DNA Polymerase in Translesion Synthesis Past Platinum–DNA Adducts in Human Fibroblasts

¹ Department of Biochemistry and Biophysics, ² Department of Pathology and Laboratory Medicine, ³ Curriculum in Toxicology, ⁴ Lineberger Comprehensive Cancer Center, and ⁵ Center for Environmental Health and Susceptibility, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and ⁶ Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York

Cisplatin, a widely used chemotherapeutic agent, has been implicated in the induction of secondary tumors in cancer patients. This drug is presumed to be mutagenic because of error-prone translesion synthesis of cisplatin adducts in DNA. Oxaliplatin is effective in cisplatin-resistant tumors, but its mutagenicity in humans has not been reported. The polymerases involved in bypass of cisplatin and oxaliplatin adducts in vivo are not known. DNA polymerase is the most efficient polymerase for bypassing platinum adducts in vitro. We evaluated the role of polymerase in translesion synthesis past platinum adducts by determining cytotoxicity and induced mutation frequencies at the hypoxanthine guanine phosphoribosyltransferase (HPRT) locus in diploid human fibroblasts. Normal human fibroblasts (NHF1) were compared with xeroderma pigmentosum variant (XPV) cells (polymerase -null) after treatment with cisplatin. In addition, XPV cells complemented for polymerase expression were compared with the isogenic cells carrying the empty expression vector. Cytotoxicity and induced mutagenicity experiments were measured in parallel in UVC-irradiated fibroblasts. We found that equitoxic doses of cisplatin induced mutations in fibroblasts lacking polymerase at frequencies 2- to 2.5-fold higher than in fibroblasts with either normal or high levels of polymerase . These results indicate that polymerase is involved in error-free translesion synthesis past some cisplatin adducts. We also found that per lethal event, cisplatin was less mutagenic than UVC. Treatment with a wide range of cytotoxic doses of oxaliplatin did not induce mutations above background levels in cells either expressing or lacking polymerase , suggesting that oxaliplatin is nonmutagenic in human fibroblasts.

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