Augustine Christina K, Yoo Jin Soo, Potti Anil, Yoshimoto Yasunori, Zipfel Patricia A, Friedman Henry S, Nevins Joseph R, Ali-Osman Francis, Tyler Douglas S
Department of Surgery, and Duke Institute for Genome Sciences and Policy, Duke University Medical Center and Durham VA Medical Center, Durham, North Carolina 27710, USA.
Clin Cancer Res. 2009 Jan 15;15(2):502-10. doi: 10.1158/1078-0432.CCR-08-1916.
Despite objective response rates of only approximately 13%, temozolomide remains one of the most effective single chemotherapy agents against metastatic melanoma, second only to dacarbazine, the current standard of care for systemic treatment of melanoma. The goal of this study was to identify molecular and/or genetic markers that correlate with, and could be used to predict, response to temozolomide-based treatment regimens and that reflect the intrinsic properties of a patient's tumor.
Using a panel of 26 human melanoma-derived cell lines, we determined in vitro temozolomide sensitivity, O(6)-methylguanine-DNA methyltransferase (MGMT) activity, MGMT protein expression and promoter methylation status, and mismatch repair proficiency, as well as the expression profile of 38,000 genes using an oligonucleotide-based microarray platform.
The results showed a broad spectrum of temozolomide sensitivity across the panel of cell lines, with IC(50) values ranging from 100 micromol/L to 1 mmol/L. There was a significant correlation between measured temozolomide sensitivity and a gene expression signature-derived prediction of temozolomide sensitivity (P < 0.005). Notably, MGMT alone showed a significant correlation with temozolomide sensitivity (MGMT activity, P < 0.0001; MGMT expression, P <or= 0.0001). The promoter methylation status of the MGMT gene, however, was not consistent with MGMT gene expression or temozolomide sensitivity.
These results show that melanoma resistance to temozolomide is conferred predominantly by MGMT activity and suggest that MGMT expression could potentially be a useful tool for predicting the response of melanoma patients to temozolomide therapy.
尽管替莫唑胺的客观缓解率仅约为13%，但它仍是针对转移性黑色素瘤最有效的单一化疗药物之一，仅次于达卡巴嗪，后者是目前黑色素瘤全身治疗的标准疗法。本研究的目的是鉴定与基于替莫唑胺的治疗方案反应相关且可用于预测该反应、并反映患者肿瘤内在特性的分子和/或基因标志物。
我们使用一组26个人类黑色素瘤衍生细胞系，测定了体外替莫唑胺敏感性、O(6)-甲基鸟嘌呤-DNA甲基转移酶（MGMT）活性、MGMT蛋白表达和启动子甲基化状态、错配修复能力，以及使用基于寡核苷酸的微阵列平台测定了38000个基因的表达谱。
结果显示细胞系组中替莫唑胺敏感性范围广泛，IC(50)值在100微摩尔/升至1毫摩尔/升之间。实测的替莫唑胺敏感性与基于基因表达特征预测的替莫唑胺敏感性之间存在显著相关性（P < 0.005）。值得注意的是，单独的MGMT与替莫唑胺敏感性显示出显著相关性（MGMT活性，P < 0.0001；MGMT表达，P ≤ 0.0001）。然而，MGMT基因的启动子甲基化状态与MGMT基因表达或替莫唑胺敏感性不一致。
这些结果表明黑色素瘤对替莫唑胺的耐药性主要由MGMT活性所致，并提示MGMT表达可能是预测黑色素瘤患者对替莫唑胺治疗反应的有用工具。
