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: T Narita, Y Koide, S Yaguchi, S Kimura, Y Izumisawa, M Takase, M Inaba, S Tsukagoshi
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 28 Issue 4 Pg. 235-40 ( 1991) ISSN: 0344-5704 [Print] Germany
• PMID: 1879040 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Piperazines
• sobuzoxane

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics)
• Biological Availability
• Cell Survival (drug effects)
• Cells, Cultured (drug effects)
• Drug Screening Assays, Antitumor
• Humans
• Male
• Mice
• Mice, Inbred Strains
• Neoplasm Transplantation
• Neoplasms, Experimental (drug therapy, metabolism)
• Piperazines (administration & dosage, pharmacokinetics)
• Transplantation, Heterologous