MST-16, a novel bis-dioxopiperazine anticancer agent, ameliorates doxorubicin-induced acute toxicity while maintaining antitumor efficacy.
MST-16 [4,4-1,2-(ethanediyl)bis(1-isobutoxycarbonyl-oxy-methyl-2,6-pipera zinedione)], recently approved as an oral anticancer drug for clinical use in Japan, was evaluated as a chemotherapeutic agent in combination with doxorubicin (DOX) in vitro and in vivo. Cytotoxicity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and murine Colon 26 and human KATO III adenocarcinoma cells were used. The combination index derived from these cytotoxic values indicated a synergistic interaction between DOX and MST-16 or its active metabolite, ICRF-154 (1,1'-ethylenedi-3,5-dioxopiperazine). A maximal tolerated dose of DOX administered to female BALB/c mice bearing a solid Colon 26 tumor resulted in severe body weight loss and diarrhea, but a limited tumor growth delay (1.8 days). However, when combined with an oral dose of MST-16, DOX-induced body weight loss and diarrhea were significantly ameliorated, and an additive tumor growth delay (8.7 days) was obtained. The LD50 of DOX administered i.p. to control female BALB/c mice increased more than 1.5-fold when combined with MST-16. Thus, MST-16 ameliorates DOX-induced acute toxicity while maintaining antitumor efficacy. These results indicate that MST-16 may be effective chemotherapy for cancer patients when combined with DOX.
Yoshida
M
M
Department of Surgery II, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Maehara
Y
Y
Sugimachi
K
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D004064:Digestive System / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology* / Q000633:toxicity*; D005260:Female; D006801:Humans; D007928:Lethal Dose 50; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011355:Prodrugs / Q000493:pharmacokinetics; D011929:Razoxane / Q000031:analogs & derivatives / Q000494:pharmacology; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D010879:Piperazines; D011355:Prodrugs; D011929:Razoxane; D004317:Doxorubicin; C000283:1,2-bis(3,5-dioxopiperazin-1-yl)ethane; C057773:sobuzoxane