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首页> 外文期刊>British Journal of Cancer >Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules
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Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules

机译：延长的替莫唑胺方案显着降低了O6-烷基鸟嘌呤-DNA烷基转移酶的活性

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Temozolomide, an oral DNA methylator that inactivates the DNA repair enzyme O6-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. O6-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?2), 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. O6-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% (PPO6-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 (90.3±5.5 vs 72.5±16.1%, P<0.045). 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.
机译：替莫唑胺是一种使DNA修复酶O6-烷基鸟嘌呤-DNA烷基转移酶（AGAT）失活的口服DNA甲基化剂，已证明其在长期治疗中具有抗癌活性。时间表的延长可能会通过累积降低细胞对AGAT介导的DNA修复和抗性的能力而导致替莫唑胺固有的细胞毒性潜能“自动增强”。进行这项研究的特征在于按两种延长的替莫唑胺方案治疗的患者外周血单核细胞（PBMC）中的AGAT失活和再生。在两项I期长期替莫唑胺研究中治疗的患者的PBMC中测量了O6-烷基鸟嘌呤-DNA烷基转移酶的活性。每天对患者进行治疗，每2周7天（附表A）或每4周21天（附表B）。研究了不同替莫唑胺剂量（75–175？mg？m？2），治疗时间（7–21天）和替莫唑胺血浆水平对AGAT灭活和再生的影响以及AGAT灭活与毒性之间的关系。 。对52例患者的PBMC中的O6-烷基鸟嘌呤-DNA烷基转移酶活性进行了连续测量。替莫唑胺治疗7天后AGAT明显失活，平均AGAT活性降低72％（PTE6-烷基鸟嘌呤-DNA烷基转移酶的失活在高剂量替莫唑胺治疗7天后大于较低剂量，并且仍显着降低7）替莫唑胺治疗14天和21天后AGAT失活在所有剂量下均相似。在连续21天的治疗方案中，严重血小板减少症患者的AGAT失活明显大于未发生血小板减少症的患者（90.3± 5.5 vs 72.5±16.1％（P <0.045）。结论：即使每日剂量相对较低，替莫唑胺的长期给药也会导致AGAT活性显着延长，这可能增强该药的抗肿瘤活性。

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