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.

该研究计划的广泛、长期目标是确定人类癌症中甲硫腺苷磷酸化酶 (MTAP) 缺陷的患病率和临床特征，并开发和应用新方法来特异性治疗 MTAP 阴性癌症。在哺乳动物细胞中，甲硫腺苷 (MTA) 在多胺合成过程中产生。 MTA 不会在正常组织中积累，但会被 MTAP 快速裂解为腺嘌呤和 5'-甲基硫核糖 1-磷酸 (MTR-1-P)。腺嘌呤和MTR-1-P被再循环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含有 MTAP，人类癌症中 MTAP 的缺乏将使我们能够开发肿瘤特异性化疗，其中 MTAP 阴性癌细胞将被选择性杀死，导致嘌呤核苷酸或蛋氨酸耗尽的药物，在在MTAP阳性正常组织的情况下，可以通过给予MTA作为嘌呤核苷酸或蛋氨酸的来源来挽救。为了检测 MTAP 阴性原发性癌症，我们开发了定量 PCR 测定法，使用 Taqman 化学法检测 MTAP 基因的纯合缺失。即使在含有 30% 正常细胞的样本中，该方法也能够诊断 MTAP 基因缺失。由于 MTAP 缺陷不仅仅归因于基因缺失，因此单克隆抗体已成功生成并准备用于免疫组织化学。为了开发选择性治疗 MTAP 阴性癌症的新方法，我们在动物模型中使用 L-丙氨酸选择性治疗 MTAP 阴性肿瘤。