Study on selective cancer chemotherapy targeting the deficiency of a purine metabolic enzyme

针对嘌呤代谢酶缺乏的选择性癌症化疗研究

基本信息

批准号：
11557205
负责人：
NOBORI Tsutomu
金额：
$ 8.13万
依托单位：
Mie University
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 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11557205/
关键词：
MTAP Taqman PCR MATP Promoter DNA methylation RT-PCR 遺伝子欠失

项目摘要

The broad, long-term objectives of this research proposal are to determine the prevalence and clinical characteristics of methylthioadenosine phosphorylase (MTAP) deficiency in human cancers and to develop and apply new methods for the specific treatment of MTAP-negative cancers.In mammalian cells, methylthioadenosine (MTA) is produced during the synthesis of the polyamines. MTA does not accumulate in normal tissues but is cleaved rapidly to adenine and 5'-methylthioribose 1-phosphate (MTR-1-P) by MTAP. The adenine and MTR-1-P are recycled to purine nucleotides and methionine. respectively. Since all normal cells or tissues are known to contain MTAP, MTAP deficiency in human cancers will enable us to develop tumor-specific chemotherapy, in which MTAP-negative cancer cells will be selectively killed with drugs causing the depletion of purine nucleotides or methionine, under conditions where MTAP-positive normal tissues can be rescued by giving MTA as the sources of purine nucleotides or methionine.In. order to detect MTAP-negative primary cancers, we have developed quantitative PCR assay to detect homozygous deletion of MTAP gene using Taqman chemistry. This method was able to diagnose MTAP gene deletion even in the samples containing 30 % normal cells. Since MTAP deficiency is not solely attributable to gene deletion, monoclonal antibodies has been generated successfully and are ready for immunohistochemistry. To develop new methods for the selective treatment of MTAP-negative cancers, we used L-alanosine to selectively treat MTAP-negative tumors in animal models.

这项研究建议的广泛，长期的目标是确定人类癌症中甲基腺苷磷酸化酶（MTAP）缺乏的普遍性和临床特征，并开发和应用新方法以特定治疗MTAP阴性癌症。 MTA不会在正常组织中积聚，而是通过MTAP迅速裂解至1-磷酸腺苷（MTR-1-P）。腺嘌呤和MTR-1-P被回收为嘌呤核苷酸和蛋氨酸。分别。由于已知所有正常细胞或组织都包含MTAP，因此人类癌症中的MTAP缺乏将使我们能够发展肿瘤特异性化学疗法，在这种情况下，在MTAP阳性正常组织中，将MTAP阴性的癌细胞选择性地杀死，从而用嘌呤核苷酸或甲基甲烷的消耗杀死，从而挽救MTAP阳性正常组织，以固定MEDINE，以固定METIN固定。为了检测MTAP阴性原发性癌症，我们开发了定量的PCR分析，以使用Taqman Chemistry检测MTAP基因的纯合缺失。即使在包含30％正常细胞的样品中，该方法也能够诊断MTAP基因缺失。由于MTAP缺乏不仅归因于基因缺失，因此单克隆抗体已成功产生，并准备进行免疫组织化学。为了开发新方法用于选择性治疗MTAP阴性癌症，我们使用L-丙氨酸在动物模型中选择性治疗MTAP阴性肿瘤。