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CELLULAR AND MOLECULAR

The Effect of O⁶-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

Istituto Dermopatico Dell'Immacolata-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy (R.P, S.F, E.P, E.B, S.D.); Institute of Medical Radiobiology, University of Zürich, Zürich, Switzerland (G.M, J.J.); and Institute of Neurobiology and Molecular Medicine, Consiglio Nazionale delle Ricerche, Rome, Italy (M.P.F.)

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 enzyme O⁶-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 of O⁶-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.

Address correspondence to: Stefania D'Atri, Istituto Dermopatico Dell'Immacolata-Istituto di Ricovero e Cura a Carattere Scientifico, Via dei Monti di Creta 104, 00167 Rome, Italy. E-mail: s.datri{at}idi.it

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