Tolcher A W, Gerson S L, Denis L, Geyer C, Hammond L A, Patnaik A, Goetz A D, Schwartz G, Edwards T, Reyderman L, Statkevich P, Cutler D L, Rowinsky E K
Institute of Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA.
Br J Cancer. 2003 Apr 7;88(7):1004-11. doi: 10.1038/sj.bjc.6600827.
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(-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. 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% (P<0.0001). Similarly, mean AGAT activity decreased by 63 and 73% after 14 and 21 days of treatment, respectively (P<0.001 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 (90.3+/-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.
替莫唑胺是一种口服DNA甲基化剂，可使DNA修复酶O(6)-烷基鸟嘌呤-DNA烷基转移酶（AGAT）失活，已证明其在延长给药方案下具有抗癌活性。延长给药方案可能通过累积降低细胞的AGAT介导的DNA修复和耐药能力，导致替莫唑胺固有细胞毒性潜力的“自我增强”。本研究旨在表征接受两种替莫唑胺延长给药方案治疗的患者外周血单核细胞（PBMC）中AGAT的失活和再生情况。在两项I期替莫唑胺延长给药研究中，对患者的PBMC进行了O(6)-烷基鸟嘌呤-DNA烷基转移酶活性检测。患者每2周每日治疗7天（方案A）或每4周每日治疗21天（方案B）。研究了不同替莫唑胺剂量（75-175mg/m²）、治疗持续时间（7-21天）和替莫唑胺血浆水平对AGAT失活和再生的影响，以及AGAT失活与毒性之间的关系。对52例患者的PBMC进行了连续的O(6)-烷基鸟嘌呤-DNA烷基转移酶活性检测。替莫唑胺治疗7天后，AGAT发生明显失活，平均AGAT活性下降72%（P<0.0001）。同样，治疗14天和21天后，平均AGAT活性分别下降63%和73%（两项比较P均<0.001）。高剂量替莫唑胺治疗7天后，O(6)-烷基鸟嘌呤-DNA烷基转移酶失活程度高于低剂量，且治疗后7天仍显著降低。然而，替莫唑胺治疗14天和21天后，所有剂量下的AGAT失活情况相似。在连续21天的给药方案中，发生严重血小板减少的患者的AGAT失活程度显著高于未发生者（90.3±5.5%对72.5±16.1%，P<0.045）。总之，即使每日剂量相对较低，延长替莫唑胺给药也会导致AGAT活性显著且持久的消耗，这可能增强该药物的抗肿瘤活性。
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