Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 28, Issue 4, pp 235–240 | Cite as

Antitumor activities and schedule dependence of orally administered MST-16, a novel derivative of bis(2,6-dioxopiperazine)

  • Toshiharu Narita
  • Yuji Koide
  • Shin-ichi Yaguchi
  • Shoji Kimura
  • Yasuhiro Izumisawa
  • Muneaki Takase
  • Makoto Inaba
  • Shigeru Tsukagoshi
Original Articles Antitumor Activities, Schedule Dependence, Bis (2,6-dioxopiperazine), MST-16
  • 40 Downloads

Summary

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 lifeprolonging 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.

Keywords

Breast Cancer Nude Mouse Therapeutic Efficacy Lung Metastasis Tumor Xenograft 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Cai JC, Shu HL, Tang CF, Komatsu T, Matsuno T, Narita T, Yaguchi S, Koide Y, Takase M (1989) Synthesis and antitumor properties ofN′-acyloxymethyl derivatives of bis(2,6-dioxopiperazines). Chem Pharm Bull (Tokyo) 37: 2976Google Scholar
  2. 2.
    Creaven PJ Allen LM, Alfold DA (1975) The bioavailability in man of ICRF-159, a new oral antineoplastic agent. J Pharm Pharmacol 27: 914Google Scholar
  3. 3.
    Creighton AM, Hellmann K, Whitecross S (1969) Antitumor activity in a series of bisdiketopiperazines. Nature 222: 384Google Scholar
  4. 4.
    Goldin A, Venditti JM, Macdonald JS, Muggia FM, Henney JE, Devita VT Jr (1981) Current results of the screening program at the Division of Cancer Treatment, National Cancer Institute. Eur J Cancer Clin Oncol 17: 129Google Scholar
  5. 5.
    Hellmann K, Burrage K (1969) Control of malignant metastases by ICRF-159. Nature 224: 273Google Scholar
  6. 6.
    Hellmann K, Newton KA, Whitmory DW, Hanman WF, Bond JV (1969) Preliminary clinical assessment of ICRF-159 in acute leukemia and lymphosarcoma. BMJ I: 822Google Scholar
  7. 7.
    Hermann EH, Witiak DT, Hellmann K, Waravdeker VS (1982) Biological properties of ICRF-159 and related bis(dioxopiperazine) compounds. Adv Pharmacol Chemother 19: 249Google Scholar
  8. 8.
    Inaba M, Tashiro T, Kobayashi T, Fujimoto S, Sakurai Y, Maruo K, Ohnishi Y, Ueyama Y, Nomura T (1986) Evaluation of response rates to various antitumor agents of human gastric tumors implanted in nude mouse. Jpn J Cancer Res 77: 190Google Scholar
  9. 9.
    Le Serve AW, Hellman K (1972) Metastasis and the normalization of tumor blood vessels by ICRF-159: a new type of drug action. BMJ I: 597Google Scholar
  10. 10.
    Narita T, Yaguchi S, Komatsu T, Takase M, Hoshino A, Inaba M, Tsukagoshi S (1990) Antitumor activity of MST-16, a novel derivative of bis(2,6-dioxopiperazine), in murine tumor models. Cancer Chemother Pharmacol 26: 193Google Scholar
  11. 11.
    Shimoyama M (1975) Cytocidal action of anticancer agents: evalation of the sensitivity of cultured animal and human cancer cells. In: Ito Y, Dutcher RM (eds) Comparative leukemic research 1973: Leukemogenesis. University of Tokyo Press, Tokyo/Karger, Basel, pp 711Google Scholar
  12. 12.
    Shimoyama M, Kimura K (1972) Quantitative clonal growth of mammalian cells: its application for quantitative study of cytocidal action of mitomycin C. Gann 63: 773Google Scholar
  13. 13.
    Trangonos F, Darzynkiewicz Z, Melamed MR (1981) Effects of the L isomer(+)-1,2-bis(3,5-dioxopiperazine-1-yl)propane on cell survival and cell cycle progression of cultured mammalian cells. Cancer Res 41: 4566Google Scholar
  14. 14.
    Wang G, Finch MD, Trevan D, Hellmann K (1981) Reduction of daunomycin toxicity by razoxane. Br J Cancer 43: 871Google Scholar
  15. 15.
    Witiak DT, Lee HJ, Goldman HD, Zwilling BS (1978) Stereoselective effects ofcis- andtrans-cyclopropyl-bis(dioxopiperazine) related to ICRF-159 on metastases of a hamster lung adenocarcinoma. J Med Chem 21: 1194Google Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • Toshiharu Narita
    • 1
  • Yuji Koide
    • 1
  • Shin-ichi Yaguchi
    • 1
  • Shoji Kimura
    • 1
  • Yasuhiro Izumisawa
    • 1
  • Muneaki Takase
    • 1
  • Makoto Inaba
    • 2
  • Shigeru Tsukagoshi
    • 2
  1. 1.Research LaboratoryZenyaku Kogyo Co., LtdTokyoJapan
  2. 2.Cancer Chemotherapy CenterJapanese Foundation for Cancer ResearchTokyoJapan

Personalised recommendations