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A study on the molecular diagnosis of antifolate resistance in leukemia cells : Establishment of anti-folate-resistant cell line and elucidation of molecular mechanisms of resistance

白血病细胞抗叶酸耐药的分子诊断研究：抗叶酸耐药细胞系的建立及耐药分子机制的阐明

基本信息

批准号：
07672502
负责人：
MIYACHI Hayato
金额：
$ 1.02万
依托单位：
Tokai University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07672502/
关键词：
anti-folate resistance methotrexate CB3717 leukemia gene

项目摘要

Antifolate resistant cell lines were established to elucidate molecular mechanisms of resistance. Effects of reduced or oxidized folates on the development of methotrexate (MTX) or N^<10>-propargyl-5,8-dideazafolic (CB3717) acid resistance were examined. An approximately 60-fold MTX-resistant CCRF-CEM developed in pteroylglutamic acid (PGA) was resistant to MTX by virtue of decreased membrance transport of the drug. Further enhancement of MTX resistance resulted in selection of an approximately 5000-fold MTX resistance as noted by increased dihydrofolate reductase (DHFR) due to gene amplification. An approximately 140-fold and subsequently 1500-fold MTX-resistant subline developed in leucovorin were resistant to MTX by virtue of increased DHFR due to gene amplification. Approximately 200-fold CB3717-resistant MOLT-3 sublines developed in PGA or leucovorin had decreased membrance transport. Only CB3717-resistant subline developed in PGA had increased thymidylate synthase due to gene amplification. Membrane transport defective anti-folate-resistant sublines showed collateral sensitivity to trimeterxate, which was reduced in the presence of leucovorin, suggesting collateral sensitivity to TMQ was caused by intracellular folate defficiency.

建立抗叶酸剂抗性细胞系以阐明抗性的分子机制。研究了还原或氧化叶酸对甲氨蝶呤（MTX）或N^<10>-炔丙基-5，8-二去氮唑啉（CB 3717）耐酸性发展的影响。在蝶酰谷氨酸（PGA）中开发的约60倍MTX抗性的CCRF-CEM由于药物的膜转运减少而对MTX具有抗性。MTX抗性的进一步增强导致约5000倍MTX抗性的选择，如通过由于基因扩增而增加的二氢叶酸还原酶（DHFR）所指出的。一个约140倍，随后1500倍的MTX耐药亚系开发的甲酰四氢叶酸凭借增加的DHFR由于基因扩增的MTX耐药。大约200倍的CB 3717抗性MOLT-3亚系在PGA或leucovorin中产生的膜转运减少。只有CB 3717抗性亚系在PGA开发增加胸苷酸合成酶由于基因扩增。膜转运缺陷型抗叶酸耐药亚系表现出对曲美曲塞的间接敏感性，在亚叶酸存在下降低，表明对TMQ的间接敏感性由细胞内叶酸缺乏引起。