APPROARCH AT MOLECULAR LEVEL FOR MECHANISMS OF MULTIDRUG-RESISTANCE AND ENHANCEMENT OF ANTICANCER DRUGS WITH HYPERTHERMIA

分子水平的多药耐药机制和热疗增强抗癌药物的研究

• 批准号: 11670890
• 负责人: KAWASAKI Shoji
• 金额: $ 2.05万
• 依托单位: OKAYAMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 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/grant/KAKENHI-PROJECT-11670890/
• 关键词: adriamycin; multidrug resistance; hyperthermia; Ehrlich ascites tumor cells; anticancer drugs; ion channel; MGMT; alkylating agent; WAF1; wortmannin; 分化度; 喉頭癌; アントシアニジン; Caイオン; Calcein; adriamycin; multidrug resistance; hyperthermia; Ehrlich ascites tumor cells; anticancer drugs; ion channel; MGMT; alkylating agent; WAF1; wortmannin; 分化度; 喉頭癌; アントシアニジン; Caイオン; Calcein

It is an important problem that tumor cells treated with anticancer drugs expressed multidrug resistance. Therfore, resistant mechanisms of varius mammalian cells were studied, MDR1 gene concerning resistance to adriamycin were appeared in our established cells of Ehrlich ascites tumor. Its resistance related to eflux pump of p-gp which is in cellular membrane, and the penetration of adriamycin into cells was affected by both of ion channels of Na^+/H^+ and Cl^-/HCO_3. Heating showed marked enhancement of cell killing effects of adriamycin. Abtitumor effects of adriamycin were tested on in vivo with or without treatment of mild hyperthermia. However, antitumor effects were shown not so much. On the other hand, efflux of adriamycin was inhibited with cepharanthine, that is, cepharanthine enhanced a killing effect of adriamycin. Antitumor effects of adriamycin were affected with intraa- and extracellure pH. Intracellular accumulation of adriamycin was small amount at acidic condition. It was depended to slow infflux of adriamycin. It is concluded that antitumor effects of adriamycin were not so large enhancement with hyperthermia as it is low pH condition in tumor and hyperthermia induced low pH more than without treatment. On the othe hand, those cells showed the other unknown resistant mechanisims to adriamycin. It is indicated that adriamysin-resistant cells of Ehrlich ascites tumor have at least two expression processes of resistance to adriamycin. There are many mechanisms on resistant to anticancer drugs. Hyperthermia enhanced markedly killing effects of alkylating agents in vitro and in vivo. The sensitivity to alkylating agents related to 06-methylguanine-DNA methyltransferase(MGMT). As MGMT expression was depressed by methylation, it is investigated that relationship between level of methylation and killing effect of alkylating agent in several human squarmous carcinoma cells. Methylation of MGMT is closely related to the sennsitivity for alkylating agents.

用抗癌药物处理多药耐药性的肿瘤细胞是一个重要的问题。因此，研究了杂多哺乳动物细胞的抗性机制，在我们已建立的Ehrlich腹水肿瘤细胞中出现了有关抗adrimycin抗性的MDR1基因。它与细胞膜中P-gp的Eflux泵有关的抗性，以及阿霉素在细胞中的渗透受到Na^+/H^+和Cl^ - /HCO_3的离子通道的影响。加热表明阿霉素的细胞杀伤作用显着增强。在体内测试了阿霉素的abtitumor效应，无论是否治疗温和的高温治疗。但是，抗肿瘤效应的表现并不多。另一方面，阿甲霉素的外排被头甲氨酸抑制，即头苯胺增强了阿霉素的杀伤作用。阿霉素的抗肿瘤作用受到细胞内和细胞外pH的影响。在酸性状态下，阿霉素的细胞内积累量很小。它取决于降低adrimycin的infflux。可以得出结论，阿霉素的抗肿瘤作用并不是高温的高度增强，因为它在肿瘤和热疗中的pH状况低，而不是未经治疗而诱导的低pH值。在Othe手上，这些细胞显示了其他对阿霉素的抗性机械电阻。据表明，Ehrlich腹水肿瘤的抗adriamysin耐药细胞至少具有两个表达对阿霉素的抗性。抗抗癌药具有许多机制。热疗在体外和体内显着杀死了烷基化剂的作用。与06-甲基鸟嘌呤-DNA甲基转移酶（MGMT）相关的烷基化剂的敏感性。由于MGMT表达因甲基化而降低，因此研究了甲基化水平与烷基化剂杀死效应之间的关系在几个人类毒虫细胞中。 MGMT的甲基化与烷基化剂的溶质性密切相关。