title: Antitumor activities and schedule dependence of orally administered MST-16, a novel derivative of bis(2,6-dioxopiperazine).
abstract: We studied bioavailability, treatment schedule dependence, and therapeutic efficacy of orally administered MST-16, a novel derivative of bis(2,6-dioxopiperazine), against murine tumors and human tumor xenografts. The rate of its intestinal absorption was about 50%, and it was immediately metabolized to its parent compound, ICRF-154. Therapeutic efficacy of MST-16 was heavily dependent on the treatment schedule: 9 daily oral administrations and treatment every 4 h on day 1 only were much more effective against s.c.-implanted L1210 leukemia than a single dose or five daily administrations giving the same total dose. Orally administered MST-16 showed potent life-prolonging effects (196%, 219% and 148%) in mice inoculated i.p. with P388, L1210 leukemia, and C-26 colon adenocarcinoma, respectively, but had no effect on B16 melanoma inoculated in the same way. MST-16 inhibited more than 80% growth of Lewis lung carcinoma, B16 melanoma, and C-38 colon adenocarcinoma implanted s.c., but had only a minor effect on M5076 fibrosarcoma. Lung metastasis of Lewis lung carcinoma was also effectively suppressed. Furthermore, MST-16 significantly inhibited growth of human colon, lung and breast cancers implanted s.c. in nude mice. We also made a kinetic analysis of the in vitro cell-killing effect by ICRF-154, the active form of MST-16 in vivo. It demonstrated a cell cycle phase-specific and time-dependent action, providing a reasonable explanation for the schedule-dependent therapeutic effect of MST-16.
authors.affiliation: Research Laboratory, Zenyaku Kogyo Co., Ltd., Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Narita
authors.forename: Y
authors.initials: Y
authors.lastname: Koide
authors.forename: S
authors.initials: S
authors.lastname: Yaguchi
authors.forename: S
authors.initials: S
authors.lastname: Kimura
authors.forename: Y
authors.initials: Y
authors.lastname: Izumisawa
authors.forename: M
authors.initials: M
authors.lastname: Takase
authors.forename: M
authors.initials: M
authors.lastname: Inaba
authors.forename: S
authors.initials: S
authors.lastname: Tsukagoshi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001682:Biological Availability; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D010879:Piperazines; C057773:sobuzoxane