Analysis of tumor suppressor gene in refractory or relapsed germ cell tumors and its therapeutic application

以顺铂为基础的联合化疗对生殖细胞肿瘤（GCT）患者的总体缓解率有所提高。尽管治愈率很高，但20- 30%的晚期GCT患者未能达到持久的完全缓解。视网膜母细胞瘤（retinoblastoma，RB）基因是一种调控细胞周期进程、分化和凋亡的基因。该基因的失活与许多人类恶性肿瘤的发生密切相关。先前的研究显示，与正常睾丸组织相比，GCT中RB mRNA和蛋白水平较低。因此，我们研究了GCTs中RB基因失活的机制，并计划开发其在GCTs中的治疗应用。在这项研究中，我们表明hGABP/E4 TF 1位点不作为正调控元件，RB基因可能在人乳腺癌细胞中在转录水平下调（Oncol Rep，2005）。此外，为了研究GCT的新的诊断标志物和潜在的治疗靶点，我们通过使用cDNA微阵列鉴定了347个通常在GCT中上调的基因（Int J Oncol，2003）。此外，我们鉴定了在GCT中显著反式激活的NALP 7，并表明NALP 7可能是开发GCT靶向治疗的有希望的候选物（Cancer Sci，2004）。在临床研究中，我们证明了伊立替康联合顺铂化疗对难治性或复发性GCT患者显示出显著的抗癌活性（Cancer，2002）。

The overall response rate of cisplatin-based combination chemotherapy for patients with germ cell tumors (GCTs) has improved. Despite the high cure rate, 20-30 percent of patients with advanced GCTs failed to achieve a durable complete response. These refractory or relapsed GCTs remain a major problem in current treatment.The tumor suppressor retinoblastoma gene (RB) is a well known regulator of cell cycle progression, differentiation and apoptosis. Inactivation of this gene is closely associated with the development of many human malignancies. Previous studies revealed lower levels of RB mRNA and protein in GCTs compared with normal testis tissue. Therefore, we investigated the mechanisms of the inactivation of the RB gene in, GCTs and planned to develop its therapeutic application for GCTs.In this study, we showed that the hGABP/E4TF1 site did not act as a positive regulatory element and the RB gene might be down-regulated at the transcriptional level in human seminoma cells (Oncol Rep, 2005). Moreover, to investigate new diagnostic markers and potential therapeutic targets for GCTs, we identified 347 genes that were commonly up-regulated in GCTs by using a cDNA microarray (Int J Oncol, 2003). Furthermore, we identified NALP7 that was significantly transactivated in GCTs and showed that NALP7 may be a promising candidate for development of targeted therapy for GCTs (Cancer Sci, 2004). In clinical study, we demonstrated that the chemotherapy with irinotecan in combination with cisplatin showed significant anticancer activity for patients with refractory or relapsed GCTs (Cancer, 2002).