Department of Neurological Surgery, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan.
Int J Oncol. 2010 Jun;36(6):1367-77. doi: 10.3892/ijo_00000621.
Malignant gliomas are highly lethal neoplasms that cannot be cured with currently available therapies. Temozolomide (TMZ) is a recently introduced alkylating agent that has yielded significant benefits and become a key agent in the treatment of high-grade gliomas. However, its survival benefit remains unsatisfactory. Understanding the molecular basis of TMZ sensitivity/resistance is necessary for improving the treatment outcome by devising strategies that are able to circumvent primary drug resistance. We therefore combined the in vitro TMZ response with microarray gene expression data to identify genes that could potentially be used to predict the response of malignant gliomas to TMZ therapy. We first obtained the individual IC50 values for TMZ in seven malignant glioma cell lines (A-172, AM-38, T98G, U-87MG, U-138MG, U-251MG and YH-13) and then identified the genes whose expression correlated most highly with TMZ sensitivity employing a cDNA microarray. We present here a list of the most highly up-regulated and down-regulated genes which may be involved in conferring TMZ sensitivity/resistance in malignant gliomas, although most of the genes have not been implicated as a causal factor in the TMZ response except MGMT. We also demonstrated and confirmed the MGMT methylation status, quantitative MGMT mRNA levels, and MGMT protein expression levels in TMZ resistant glioma cells in vitro. Our results are thus consistent with previous studies and suggest that a dominant mechanism conferring sensitivity/resistance to TMZ exists in malignant glioma cells. Although the present study dose have several limitations, our reported candidate genes could represent not only potential molecular markers for TMZ sensitivity/resistance but also chemotherapy targets. Furthermore, the present study could provide a foundation for alternative therapeutic strategies including novel combination treatments that incorporate additional reagents directed at overcoming resistance to TMZ.
恶性神经胶质瘤是高度致命的肿瘤，目前的治疗方法无法治愈。替莫唑胺（TMZ）是一种新引入的烷化剂，已带来显著的益处，并成为高级神经胶质瘤治疗的关键药物。然而，其生存获益仍不令人满意。了解 TMZ 敏感性/耐药性的分子基础对于通过设计能够规避原发性耐药的策略来改善治疗结果是必要的。因此，我们将体外 TMZ 反应与微阵列基因表达数据相结合，以鉴定可能用于预测恶性神经胶质瘤对 TMZ 治疗反应的基因。我们首先获得了七种恶性神经胶质瘤细胞系（A-172、AM-38、T98G、U-87MG、U-138MG、U-251MG 和 YH-13）中 TMZ 的个体 IC50 值，然后使用 cDNA 微阵列鉴定了与 TMZ 敏感性相关性最高的基因。我们在这里列出了可能参与赋予恶性神经胶质瘤 TMZ 敏感性/耐药性的高度上调和下调基因的列表，尽管除了 MGMT 之外，大多数基因都没有被认为是 TMZ 反应的因果因素。我们还在体外 TMZ 耐药性神经胶质瘤细胞中证明并证实了 MGMT 甲基化状态、定量 MGMT mRNA 水平和 MGMT 蛋白表达水平。因此，我们的结果与先前的研究一致，并表明恶性神经胶质瘤细胞中存在赋予 TMZ 敏感性/耐药性的主导机制。尽管本研究存在一些局限性，但我们报告的候选基因不仅可以代表 TMZ 敏感性/耐药性的潜在分子标志物，也可以作为化疗靶点。此外，本研究为替代治疗策略提供了基础，包括纳入针对克服 TMZ 耐药性的其他试剂的新联合治疗。
