RT Journal Article SR Electronic T1 The Effect of O 6-Alkylguanine-DNA Alkyltransferase and Mismatch Repair Activities on the Sensitivity of Human Melanoma Cells to Temozolomide, 1,3-bis(2-Chloroethyl)1-nitrosourea, and Cisplatin JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 661 OP 668 DO 10.1124/jpet.102.043950 VO 304 IS 2 A1 Rita Pepponi A1 Giancarlo Marra A1 Maria Pia Fuggetta A1 Sabrina Falcinelli A1 Elena Pagani A1 Enzo Bonmassar A1 Josef Jiricny A1 Stefania D'Atri YR 2003 UL http://jpet.aspetjournals.org/content/304/2/661.abstract AB The prognosis of advanced melanoma is generally poor, because this tumor commonly exhibits intrinsic or acquired resistance to chemotherapy. In an attempt to identify the underlying causes of this resistance, we studied the roles played by the DNA repair enzymeO6-alkylguanine-DNA alkyltransferase (OGAT) and the mismatch repair (MMR) system in the sensitivity of melanoma cells to temozolomide (TMZ), 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), or cis-diamminedichloroplatinum(II) (CDDP). To this end, OGAT levels and MMR efficiency of extracts of nine melanoma cell lines and selected clones derived from four of these lines were determined and correlated with the sensitivity of the respective cells to these drugs. The effectiveness ofO6-benzylguanine (BG), a specific OGAT inhibitor, in potentiating TMZ- or BCNU-mediated cytotoxicity was also evaluated. Our results demonstrate that MMR efficiency and OGAT levels strongly affect melanoma cell sensitivity to TMZ. In MMR-proficient cells, a direct correlation between OGAT levels and TMZ IC50 values was found. When OGAT activity was inhibited with BG, the sensitivity of these cells to TMZ increased and was then dictated largely by their MMR efficiency. MMR-deficient cells were highly resistant to the drug irrespective of their OGAT levels. Although OGAT activity and MMR status seemed to be the major determinants of melanoma sensitivity to TMZ, this was not the case for BCNU and CDDP; resistance to the latter drugs clearly involves processes other than the two DNA repair pathways analyzed in this study. The American Society for Pharmacology and Experimental Therapeutics