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

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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.