A single cycle of treatment with temozolomide, alone or combined with O6-benzylguanine, induces strong chemoresistance in melanoma cell clones in vitro: role of O6-methylguanine-DNA methyltransferase and the mismatch repair system
| Autor: | Enzo Bonmassar, Rita Pepponi, Patrizia Caporaso, Joseph Jiricny, Simona Caporali, Stefania D'Atri, Giancarlo Marra, Franziska Fischer, Ester Alvino, Daniele Castiglia, Pedro Miguel Lacal, Giovanna Zambruno |
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| Přispěvatelé: | University of Zurich, D'Atri, S |
| Rok vydání: | 2006 |
| Předmět: |
Cancer Research
Guanine Methyltransferase DNA Repair Base Pair Mismatch DNA repair Antineoplastic Agents Biology O(6)-Methylguanine-DNA Methyltransferase chemistry.chemical_compound Temozolomide Tumor Cells Cultured medicine Humans 1306 Cancer Research Enzyme Inhibitors Promoter Regions Genetic Melanoma neoplasms 10061 Institute of Molecular Cancer Research O-6-methylguanine-DNA methyltransferase DNA Methylation Cell cycle medicine.disease Molecular biology digestive system diseases Up-Regulation Dacarbazine Oncology chemistry Drug Resistance Neoplasm 570 Life sciences biology 2730 Oncology DNA mismatch repair Deoxycytidine medicine.drug |
| Zdroj: | International Journal of Oncology. |
| ISSN: | 1791-2423 1019-6439 |
| DOI: | 10.3892/ijo.29.4.785 |
| Popis: | Clinically achievable concentrations of temozolomide (TMZ) produce cytotoxic effects only in mismatch repair (MMR)-proficient cells endowed with low O6-methylguanine-DNA methyltransferase (MGMT) activity. Aim of the present study was to investigate the molecular mechanisms underlying acquired resistance of melanoma cells to TMZ and the effect of O6-benzylguanine (BG), a specific MGMT inhibitor, on the development of a TMZ-resistant phenotype. Three MMR-proficient melanoma cell clones with low or no MGMT activity were treated daily for 5 days with 50 micromol/l TMZ, alone or in combination with 5 micromol/l BG. Parental clones and sublines established after one or four cycles of treatment were analyzed for sensitivity to TMZ or TMZ+BG and for other parameters. The sublines established after one cycle of TMZ or TMZ+BG exhibited a marked increase in MGMT activity and resistance to TMZ alone. BG only partially reversed acquired resistance to the drug. In some cases, alterations in the MMR system accounted for MGMT-independent resistance to TMZ. Up-regulation of MGMT activity was associated with either demethylation of the MGMT promoter or hypermethylation of the body of the gene, and partially reversed by 5-aza-2'-deoxycytidine. The sublines established after four cycles of TMZ or TMZ+BG did not show a further increase in resistance to TMZ alone. However, two out of three sublines established after TMZ+BG treatment exhibited increased resistance to TMZ+BG. In conclusion, our data demonstrate that a single cycle of TMZ is sufficient to induce high levels of drug resistance in melanoma clones, principally, but not exclusively, via up-regulation of MGMT expression. Exposure to TMZ+BG favors the development of MGMT-independent mechanisms of TMZ resistance. |
| Databáze: | OpenAIRE |
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