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

难治性或复发性生殖细胞肿瘤抑癌基因分析及其治疗应用

基本信息

批准号：
14370519
负责人：
MIKI Tsuneharu
金额：
$ 8.7万
依托单位：
Kyoto Prefectural University of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370519/
关键词：
refractory or relapsed GCTs retinoblastoma gene promoter tumor suppressor gene E4TF1 NALP7 irinotecan cisplatin マイクロアレイ精巣腫瘍 CDDP CPT-11 難治性分化胎児性癌 Teratoma アポトーシス

项目摘要

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).

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。这些难治性或复发性 GCT 仍然是当前治疗中的一个主要问题。肿瘤抑制视网膜母细胞瘤基因 (RB) 是众所周知的细胞周期进展、分化和凋亡的调节因子。该基因的失活与许多人类恶性肿瘤的发生密切相关。先前的研究表明，与正常睾丸组织相比，GCT 中 RB mRNA 和蛋白质的水平较低。因此，我们研究了GCT中RB基因失活的机制，并计划开发其在GCT中的治疗应用。在这项研究中，我们表明hGABP/E4TF1位点并不充当正向调控元件，并且RB基因在人精原细胞瘤细胞中可能在转录水平上下调（Oncol Rep，2005）。此外，为了研究 GCT 的新诊断标记和潜在治疗靶点，我们使用 cDNA 微阵列鉴定了 GCT 中通常上调的 347 个基因（Int J Oncol，2003）。此外，我们鉴定了在 GCT 中显着反式激活的 NALP7，并表明 NALP7 可能是开发 GCT 靶向治疗的有希望的候选者（Cancer Sci，2004）。在临床研究中，我们证明伊立替康联合顺铂化疗对难治性或复发性 GCT 患者显示出显着的抗癌活性（Cancer，2002）。