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Study on gene analysis and gene expresssion associated with differentiation in testicular germ cell tumor

睾丸生殖细胞肿瘤分化相关基因分析及基因表达研究

基本信息

批准号：
11470341
负责人：
MIKI Tsuneharu
金额：
$ 7.23万
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：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470341/
关键词：
Testicular Tumor Gene WT1 Induction of Differentiation Apoptosis Chemotherapy Irinotecan Cisplatin Embryonal carcinoma Teratoma WT1遺伝子 VD3 p27プロモーター p53遺伝子 WAF1 Apo-2リガンド Bnip3L

项目摘要

We measured the expression level of WT1 mRNA in 34 testicular tumors by quantitative RT-PCR.The level of WT1 mRNA expression in high stage testicular tumors was higher than that in low stage tumors. There was no correlation between the level of WT1 mRNA expression and grade of testicular tumors.The maturation of TTSC-3 and TTSC-5 human testicular embryonal carcinoma (EC) lines by cisplatin was examined. When cisplatin at 1 mg/kg/week was injected intraperitoneally into TTSC-3-bearing mice, the low dose cisplatin had no effect on tumor growth. However, injection of cisplatin at 5 mg/kg/week induced marked regression of the tumor. In contrast, cisplatin at 3 mg/kg/week had a modest inhibitory effect on tumor growth and induced tumor dormancy. Histological examination revealed that 5 weeks after injection of cisplatin ( 3 mg/kg/week), primitive mesenchymal like cells increased, and 10 weeks after cisplatin injection, cartilage and well-developed glands (teratoma) were observed. Of 1176 different human cDNA transcripts in cisplatin-treated TTSC-3, three genes (tumor necrosis factor receptor 1, caspase 8 and Apaf1), which are associated with apoptosis, were found to be markedly increased.The chemotherapy with irinotecan in combination with cisplatin or nedaplatin, a derivative of cisplatin, was investigated as salvage chemotherapy for GCT.Twenty patients were entered onto the study, and 18 were assessable for response and toxicity. The response rate was 56 % (5 complete responses and 5 partial responses). Eight patients remain alive without disease. However, 5 patients died of the disease, and 1 patient died of brain glioma. The 5-year survival rate was approximately 55 %. Myelosuppression was the major toxicity, but was quite manageable. This study demonstrates that the chemotherapy with irinotecan in combination with cisplatin or nedaplatin showed a significant anticancer activity for patients with refractory GCT, without serious side effects.

采用定量RT-PCR方法检测了34例睾丸肿瘤组织中WT 1 mRNA的表达水平，发现高分期睾丸肿瘤组织中WT 1 mRNA的表达水平高于低分期睾丸肿瘤组织。WT 1 mRNA表达水平与睾丸肿瘤分级无关，用顺铂诱导人睾丸胚胎癌（EC）细胞株TTSC-3和TTSC-5成熟。当顺铂以1 mg/kg/周腹腔注射到携带TTSC-3的小鼠中时，低剂量顺铂对肿瘤生长没有影响。然而，以5 mg/kg/周注射顺铂诱导肿瘤显著消退。相比之下，3 mg/kg/周的顺铂对肿瘤生长具有中度抑制作用并诱导肿瘤休眠。组织学检查显示，注射顺铂（3 mg/kg/周）后5周，原始间充质样细胞增加，注射顺铂后10周，观察到软骨和发育良好的腺体（畸胎瘤）。在顺铂处理的TTSC-3中的1176种不同的人cDNA转录物中，与细胞凋亡相关的肿瘤坏死因子受体1（tumor necrosis factor receptor 1，caspase 8）和Apaf 1的表达显著增加。伊立替康联合顺铂或奈达铂（顺铂的衍生物）作为GCT的挽救性化疗进行了研究。20例患者入组研究，18例可评价反应和毒性。应答率为56%（5例完全应答和5例部分应答）。8名患者仍然活着，没有疾病。但5例患者死于该病，1例患者死于脑胶质瘤。5年生存率约为55%。骨髓抑制是主要毒性，但相当可控。本研究表明，伊立替康联合顺铂或奈达铂化疗对难治性GCT患者显示出显著的抗癌活性，且无严重副作用。