MST-16, a novel bis-dioxopiperazine anticancer agent, ameliorates doxorubicin-induced acute toxicity while maintaining antitumor efficacy

Motofumi Yoshida, Yoshihiko Maehara, Keizo Sugimachi

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

MST-16 [4,4-1,2-(ethanediyl)bis(1-isobutoxycarbonyloxy-methyl-2,6- piperazinedione)], 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.

Original languageEnglish
Pages (from-to)4295-4300
Number of pages6
JournalClinical Cancer Research
Volume5
Issue number12
Publication statusPublished - Dec 1 1999

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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