Temozolomide pharmacodynamics in patients with metastatic melanoma: DNA damage and activity of repair enzymes 6-alkylguanine alkyltransferase and poly(ADP-ribose) polymerase-1
Temozolomide pharmacodynamics in patients with metastatic melanoma: DNA damage and activity of repair enzymes 6-alkylguanine alkyltransferase and poly(ADP-ribose) polymerase-1
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DOI：
10.1158/1078-0432.ccr-04-2353
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发表时间：
2005-05-01
影响因子：
11.5
通讯作者：
Curtin, NJ
中科院分区：
文献类型：
--
作者：
Plummer, ER;Middleton, MR;Curtin, NJ
目的：替莫唑胺是一种用于治疗黑色素瘤的DNA甲基化剂，可诱导DNA损伤，通过O-6-烷基鸟嘌呤烷基转移酶（AT酶）和聚（ADP-核糖）聚合酶-1（PARP-1）依赖性碱基切除修复来修复。目前的研究是为了确定替莫唑胺对DNA完整性和相关修复酶的影响，作为替莫唑胺与PARP抑制剂联合治疗的I期试验的前奏。实验设计：替莫唑胺（200 mg/m2口服给药）给予12例转移性恶性黑色素瘤患者。分析外周血淋巴细胞（PBL）的PARP活性、DNA单链断裂、AT酶水平和DNA甲基化。PARP活性也测定在肿瘤活检从9 12例和健康志愿者PBLs。结果：替莫唑胺的药代动力学与以前的报告是一致的。替莫唑胺治疗导致N-7-甲基鸟嘌呤水平显著和持续升高，AT酶活性适度和持续降低，PBL中DNA链断裂和PARP活性适度和短暂增加。PARP-1在肿瘤匀浆中的活性是可变的（8218 +/- 599 pmol PAR单体/mg蛋白质），并没有受到temozolomidetreatment.Conclusions的一贯影响：这里报道的temozolomide的效果是一致的，在以前的研究与temozolomide和类似的药物，达卡巴嗪，证明了一个代表性的患者人群进行了调查。此外，替莫唑胺治疗不会抑制PARP活性，因此，这种新验证的药效学试验适用于PARP-1抑制剂与替莫唑胺联合治疗的原理验证I期试验。
Purpose: Temozolomide, a DNA methylating agent used to treat melanoma, induces DNA damage, which is repaired by O-6-alkylguanine alkyltransferase (ATase) and poly (ADP-ribose) polymerase-1 (PARP-1)-dependent base excision repair. The current study was done to define the effect of temozolomide on DNA integrity and relevant repair enzymes as a prelude to a phase I trial of the combination of temozolomide with a PARP inhibitor.Experimental Design: Temozolomide (200 mg/m(2) oral administration) was given to 12 patients with metastatic malignant melanoma. Peripheral blood lymphocytes (PBL) were analyzed for PARP activity, DNA single-strand breakage, ATase levels, and DNA methylation. PARP activity was also measured in tumor biopsies from 9 of 12 patients and in PBLs from healthy volunteers.Results: Temozolomide pharmacokinetics were consistent with previous reports. Temozolomide therapy caused a substantial and sustained elevation of N-7-methylguanine levels, a modest and sustained reduction in ATase activity, and a modest and transient increase in DNA strand breaks and PARP activity in PBLs. PARP-1 activity in tumor homogenates was variable (8218 +/- 599 pmol PAR monomer/mg protein) and was not consistently affected by temozolomide treatment.Conclusions: The effect of temozolomide reported here are consistent with those documented in previous studies with temozolomide and similar drug, dacarbazine, demonstrating that a representative patient population was investigated. Furthermore, PARP activity was not inhibited by temozolomide treatment and this newly validated pharmacodynamic assay is therefore suitable for use in a proof-of-principle phase I trial a PARP-1 inhibitor in combination with temozolomide.