Antitumor activity of temozolomide combined with irinotecan is partly independent of O6-methylguanine-DNA methyltransferase and mismatch repair phenotypes in xenograft models.
Antitumor activity of temozolomide combined with irinotecan is partly independent of O6-methylguanine-DNA methyltransferase and mismatch repair phenotypes in xenograft models.
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发表时间：
2000-10
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通讯作者：
P. Houghton;C. Stewart;P. Cheshire;L. Richmond;M. Kirstein;C. Poquette;M. Tan;H. Friedman;T. Brent
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作者：
P. Houghton;C. Stewart;P. Cheshire;L. Richmond;M. Kirstein;C. Poquette;M. Tan;H. Friedman;T. Brent
替莫唑胺联合伊立替康(CPT-11)对8个独立的异种移植瘤(4个神经母细胞瘤，3个横纹肌肉瘤和1个胶质母细胞瘤)的活性进行了评估。在所有研究中，替莫唑胺口服。每日连续5天/周期，在初步研究中发现是最佳给药方案。静脉注射伊立替康。疗程5天，连续2周/周期。治疗周期为每21天重复一次，共3个周期，共8周。替莫唑胺和CPT-11联合在四个神经母细胞瘤、两个横纹肌肉瘤和胶质母细胞瘤株中诱导完全反应。在四种肿瘤细胞系中，联合用药的活性显著高于单独给药的活性。值得注意的是，这种相互作用似乎独立于肿瘤MGMT或错配修复表型，表明协同作用的机制可能独立于替莫唑胺的O6甲基化。药代动力学研究表明，这两种药物之间没有可检测到的相互作用。此外，联合应用CPT-11似乎可以降低替莫唑胺对荷瘤小鼠的毒性。
The activity of temozolomide combined with irinotecan (CPT-11) was evaluated against eight independent xenografts (four neuroblastomas, three rhabdomyosarcomas, and one glioblastoma). In all studies, temozolomide was administered p.o. daily for 5 consecutive days/cycle, found in preliminary studies to be the optimal schedule for administration. Irinotecan was administered i.v. for 5 days for 2 consecutive weeks/cycle. Treatment cycles were repeated every 21 days for a total of three cycles over 8 weeks. In combination, temozolomide and CPT-11 induced complete responses in four neuroblastomas, two rhabdomyosarcomas, and the glioblastoma line. The activity of the combination was significantly greater than the activity of either agent administered alone in four tumor lines. Of interest, the interaction appeared independent of tumor MGMT or mismatch repair phenotype, suggesting that the mechanism of synergy may be independent of O6-methylation by temozolomide. Pharmacokinetic studies indicated no detectable interaction between these two agents. Further, coadministration of CPT-11 appeared to reduce the toxicity of temozolomide in tumor-bearing mice.