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A single cycle of treatment with temozolomide, alone or combined with O(6)-benzylguanine, induces strong chemoresistance in melanoma cell clones in vitro: role of O(6)-methylguanine-DNA methyltransferase and the mismatch repair system


Alvino, E; Castiglia, D; Caporali, S; Pepponi, R; Caporaso, P; Lacal, P M; Marra, G; Fischer, F; Zambruno, G; Bonmassar, E; Jiricny, J; D'Atri, S (2006). A single cycle of treatment with temozolomide, alone or combined with O(6)-benzylguanine, induces strong chemoresistance in melanoma cell clones in vitro: role of O(6)-methylguanine-DNA methyltransferase and the mismatch repair system. International Journal of Oncology, 29(4):785-797.

Abstract

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.

Abstract

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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2006
Deposited On:07 Jul 2010 09:03
Last Modified:05 Apr 2016 14:09
Publisher:Spandidos
ISSN:1019-6439
Official URL:http://www.spandidos-publications.com/ijo/article.jsp?article_id=ijo_29_4_785
PubMed ID:16964376

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