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.
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 O(6)-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 O(6)-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 IC(50) 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.
Pepponi
Rita
R
Istituto Dermopatico Dell'Immacolata-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
Marra
Giancarlo
G
Fuggetta
Maria Pia
MP
Falcinelli
Sabrina
S
Pagani
Elena
E
Bonmassar
Enzo
E
Jiricny
Josef
J
D'Atri
Stefania
S
D019883:Alkyl and Aryl Transferases / Q000378:metabolism*; D020137:Base Pair Mismatch / Q000187:drug effects; D002330:Carmustine / Q000494:pharmacology* / Q000627:therapeutic use; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D002999:Clone Cells; D011088:DNA Ligases / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology*; D000077204:Temozolomide; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D003606:Dacarbazine; D019883:Alkyl and Aryl Transferases; C050956:DNA alkyltransferase; D011088:DNA Ligases; D002945:Cisplatin; D002330:Carmustine; D000077204:Temozolomide