O6-Methylguanine-DNA methyltransferase in pretreatment tumour biopsies as a predictor of response to temozolomide in melanoma

Middleton, Mark R.; Lunn, J M; Morris, Charles; Rustin, G. J. S.; Wedge, Stephen R.; Brampton, MH; Lind, Michael; Lee, Siow Ming; Newell, David R.; Bleehen, Norman M.; Newlands, ES; Calvert, A. Hilary; Margison, Geoffrey P.; Thatcher, Nick

doi:10.1038/bjc.1998.654

Cited by 78 publications

(52 citation statements)

References 13 publications

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“…In addition, both failure-free survival and overall survival were significantly longer following BCNU treatment in patients with brain tumours that expressed low to intermediate levels of AGAT (o60 000 molecules per nucleus) compared to those with tumours expressing high levels of AGAT (progression-free survival, 6 vs 3 months (P ¼ 0.008); overall survival, 29 vs 8 months (Po0.0002)) (Jaeckle et al, 1998). This relation of AGAT expression and clinical outcome in brain tumour patients, a tumour site in which methylating/alkylating agents have some utility, may not be applicable in other malignancies, where the mechanisms of chemotherapy resistance may be independent of AGAT expression (Middleton et al, 1998). In the present study, AGAT activity decreased by 80 and 75% following 7 and 21 days of treatment with temozolomide on well-tolerated dose-schedules.…”

Section: Discussionmentioning

confidence: 99%

Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules

Tolcher

Gerson

Lairon³

et al. 2003

Br J Cancer

343

212

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Temozolomide, an oral DNA methylator that inactivates the DNA repair enzyme O 6 -alkylguanine-DNA alkyltransferase (AGAT), has demonstrated anticancer activity on protracted schedules. Protracted schedules may lead to an 'autoenhancement' of temozolomide's inherent cytotoxic potential by cumulative reduction of the cell's capacity for AGAT-mediated DNA repair and resistance. This study was undertaken to characterise AGAT inactivation and regeneration in the peripheral blood mononuclear cells (PBMCs) of patients treated on two protracted temozolomide schedules. O 6 -alkyl guanine-DNA alkyltransferase activity was measured in the PBMCs of patients treated on two phase I protracted temozolomide studies. Patients were treated daily for either 7 days every 2 weeks (Schedule A) or 21 days every 4 weeks (Schedule B). The effects of various temozolomide doses (75 -175 mg m À2 ), treatment duration (7 -21 days), and temozolomide plasma levels on AGAT inactivation and regeneration, as well as the relation between AGAT inactivation and toxicity, were studied. O 6 -alkyl guanine-DNA alkyltransferase activity in PBMCs was measured serially in 52 patients. Marked inactivation of AGAT occurred following 7 days of temozolomide treatment, with mean AGAT activity decreasing by 72% (Po0.0001). Similarly, mean AGAT activity decreased by 63 and 73% after 14 and 21 days of treatment, respectively (Po0.001 for both comparisons). O 6 -alkyl guanine-DNA alkyltransferase inactivation was greater after 7 days of treatment with higher doses of temozolomide than lower doses and remained markedly reduced 7 days post-treatment. However, AGAT inactivation following temozolomide treatment for 14 and 21 days was similar at all doses. On the continuous 21-day schedule, AGAT inactivation was significantly greater in patients who experienced severe thrombocytopenia than those who did not (90.375.5 vs 72.5716.1%, Po0.045). In Conclusion, protracted administration of temozolomide, even at relatively low daily doses, leads to significant and prolonged depletion of AGAT activity, which may enhance the antitumour activity of the agent.

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Section: Discussionmentioning

confidence: 99%

Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules

Tolcher

Gerson

Lairon³

et al. 2003

Br J Cancer

343

212

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“…22 However, previous studies could not prove the association between MGMT concentration in tumors prior to treatment and sensitivity of tumors to the methylating agent temozolamide in melanoma patients. 24 Other studies of the same group demonstrated, in contrast, improved survival in patients with tumors expressing low levels of MGMT after treatment with temozolamide. 25 The relationship between MGMT levels, activity and response to chemotherapy with alkylating agents in melanoma patients needs further investigation.…”

Section: Drug Resistance Mediated By Altered Dna Repairmentioning

confidence: 97%

Drug-resistance in human melanoma

Helmbach¹,

Rossmann²,

Kern³

et al. 2001

Int. J. Cancer

164

137

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Advanced malignant melanoma has a poor prognosis since chemotherapy is mostly ineffective due in part to the intrinsic and/or extrinsic resistance of melanoma cells to systemic treatment with anti-neoplastic agents. The reasons for the chemoresistant phenotype are unknown. The relevance of well-analyzed drug-resistance mechanisms, e.g., intracellular/ extracellular transport and induction of certain enzyme systems, is reviewed. Most anti-cancer drugs kill susceptible cells through induction of apoptosis. Therefore, it appears that differences in the apoptotic pathways which lead to apoptotic deficiency may account for the ability of some tumor cells to resist drug therapy. Human melanomas, which are characteristically drug-resistant, are more likely to have altered apoptotic pathways and fewer pro-apoptotic molecules. Tumor cells with these characteristics are seldom sensitive to drugs. The complexity of the molecular variants involved in signal transduction along apoptotic pathways suggests that the cell may have a variety of possibilities for regulating apoptosis and generating apoptotic deficiency. Thus, apoptosis and apoptotic deficiency should be analyzed to better clarify the mechanisms of melanoma resistance.

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“…Cancer cells may acquire resistance to temozolomide by a number of mechanisms, including overexpression of O 6 -alkylguanine-DNA alkyltransferase (Lee et al, 1994;Middleton et al, 1998), deficiency or mutation in the mismatch repair (MMR) pathway (D'Atri et al, 1998) and increased expression of proteins that inhibit apoptosis, such as Bcl-2 (Selzer et al, 1998). Temozolomide is well tolerated (Newlands et al, 1992;O'Reilly et al, 1993;Bleehen et al, 1995;Dhodapkar et al, 1997), with thrombocytopaenia as the main toxicity.…”

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confidence: 99%

Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations

et al. 2005

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The purpose of this study was to determine activity of temozolomide combined with paclitaxel or epothilone B in vitro, and to investigate the combination of temozolomide with paclitaxel in a Phase I clinical trial. Melanoma cell lines A375P and DX3 were treated with temozolomide and either paclitaxel or epothilone B. Combination indices were determined to assess the degree of synergism. In a clinical study, 21 patients with malignant melanoma were treated with increasing doses of temozolomide (orally, days 1 -5), in combination with a fixed dose of paclitaxel (i.v. infusion day 1), followed by dose escalation of the latter drug. Cycles of treatment were repeated every 3 weeks. Pharmacokinetics of both agents were determined on day 1, with temozolomide pharmacokinetics also assessed on day 5. All three compounds were active against the melanoma cell lines, with epothilone B being the most potent. There was a strong degree of synergism between temozolomide and either paclitaxel or epothilone B. In the clinical study, no pharmacokinetic interaction was observed between temozolomide and paclitaxel. Dose escalation of both drugs to clinically active doses was possible, with no dose-limiting toxicities observed at 200 mg m À2 day À1 temozolomide and 225 mg m À2 day À1 paclitaxel. There were two partial responses out of 15 evaluable patients. One patient remains alive and symptom-free at 4 years after treatment. Temozolomide and paclitaxel may be administered safely at clinically effective doses. Further evaluation of these combinations in melanoma is warranted.

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O6-Methylguanine-DNA methyltransferase in pretreatment tumour biopsies as a predictor of response to temozolomide in melanoma

Cited by 78 publications

References 13 publications

Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules

Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules

Drug-resistance in human melanoma

Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations

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