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

以顺铂为主的联合化疗对生殖细胞肿瘤(GCTS)患者的总体有效率有所提高。尽管治愈率很高，但20-30%的晚期GCTS患者未能实现持久的完全缓解。这些难治性或复发的视网膜母细胞瘤仍然是目前治疗中的一个主要问题。肿瘤抑制基因视网膜母细胞瘤(retinoblastoma，Rb)是众所周知的细胞周期进展、分化和凋亡的调节基因。该基因的失活与许多人类恶性肿瘤的发生密切相关。以往的研究表明，与正常睾丸组织相比，GCTS中Rb的mRNA和蛋白水平较低。因此，我们研究了Rb基因在GCTS中失活的机制，并计划开发其在GCTs中的治疗应用。在本研究中，我们发现在人类精原细胞瘤细胞中，hGABP/E4TF1位点不起正向调控元件的作用，Rb基因可能在转录水平上下调(Onol Rep，2005)。此外，为了研究GCTS的新诊断标记物和潜在的治疗靶点，我们利用cDNA微阵列鉴定了347个在GCTS中普遍上调的基因(Int J Onol，2003)。此外，我们鉴定了在GCTS中显著反式激活的NALP7，并表明NALP7可能是开发GCTS靶向治疗的一个有前途的候选基因(癌症科学，2004)。在临床研究中，我们证明了伊立替康联合顺铂对难治性或复发性GCTS患者具有显著的抗癌活性(癌症，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).