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Antitumor activity of intoplicine (RP 60475, NSC 645008), a new benzo-pyrido-indole: evaluation against solid tumors and leukemias in mice

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Summary

Intoplicine (RP 60475, NSC 645008) is a new 7H-benzo[e]pyrido[4,3-b] indole derivative which interacts with DNA and inhibits both topoisomerases I and II.In vitro it was found cytotoxic against various cell types with greater cytotoxicity towards solid tumor cells. We report here the anticancer activity of RP 60475 against a variety of transplantable tumors of mice, and also its cross-resistance profile in leukemias. The end points used were % T/C (median tumor weight of the Treated over the Control × 100) and logCK (log10 cell kill total). RP 60475 administered i.v. was found schedule-independent with a peak plasma level problem. It had a good therapeutic index and host recovery usually occurred 7.5 days post last treatment. RP 60475 was found to be highly active against early stage colon 38 (T/C=0%, 2.9 logCK) and could induce 5/5 complete regressions of advanced stage tumor. It was found active against colon adenocarcinoma 51 (T/C=3.6%, 1.9 logCK) and colon carcinoma 26 (T/C=11.7%, 1.2 logCK). Most of the mammary adenocarcinomas were found very responsive, MA16/C (T/C=0%, 2.8 logCK), MA14/A (T/C=0%, 1.4 logCK), MA13/C (T/C=0%, 3.1 log CK) and MA44 (T/C=34%). Excellent activity was also observed against early stage pancreatic ductal adenocarcinoma 03 (T/C=0%) and RP 60475 could achieve 5/5 complete regressions of upstaged tumor. Activity was also obtained on Glasgow osteogenic sarcoma (T/C=0%, 3.3 logCK), on B16 melanoma (T/C=14%, 1.3 logCK) and to a lesser extent on Lewis lung carcinoma (T/C=33.2%). Evaluation of RP 60475 against leukemia sublines with acquired resistance, revealed that L1210/cisplatin and L1210/BCNU were not cross-resistant to RP 60475 whereas P388/vincristine was partially cross-resistant to RP 60475 and P388/doxorubicin was cross-resistant to RP 60475. Based on RP 60475 broad activity against transplantable tumors of mice, its effectiveness against some resistant sublines, its original mechanism of action and its acceptable toxicological profile, this compound was selected for clinical trials.

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References

  1. 1.

    Schneider E, Hsiang YH, Liu LF: DNA topoisomerases as anticancer drug targets. Advances in Pharmacology,21:149–183, 1990

  2. 2.

    Hsiang YH, Hertzberg R, Hecht S, Liu LF: Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem, 260:14873–14878, 1985

  3. 3.

    Kunimoto T, Nitta K, Tanaka T, Uehara N, Baba H, Takeuchi M, Yokokura T, Sawada S, Miyasaka T, Mutai M: Antitumor activity of 7-ethyl-10-[4-(l-piperidino)-1-pi-peridino]carbonyloxy-camptothecin, a novel water-soluble derivative of camptothecin, against murine tumors. Cancer Research 47:5944–5947, 1987

  4. 4.

    Kingsbury WD, Boehm JC, Jakas DR, Holden KG, Hecht SM, Gallagher G, Caranfa MJ, McCabe FL, Faucette LF, Johnson RK, Hertzberg RP: Synthesis of water-soluble (aminoalkyl)camptothecin analogues: inhibition of topoisomerase I and antitumor activity. J Med Chem 34:98–107, 1991

  5. 5.

    Tewey KM, Rowe TC, Yang L, Halligan BD, Liu LF: Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science 226:466–468, 1984

  6. 6.

    Marshall B, Ralph RK: The mechanism of action of mAM-SA. Adv Cancer Res 44:267–293, 1985

  7. 7.

    Tewey KM, Chen GL, Nelson EM, Liu LF: Intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II. J Biol Chem 259:9182–9187, 1984

  8. 8.

    Chen GL, Yang L, Rowe TC, Halligan BD, Tewey KM, Liu LF: Nonintercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II. J Biol Chem 259:13560–13566, 1984

  9. 9.

    Kohn KW, Pommier Y, Kerrigan D, Markovits J, Covey JM: Topoisomerase II as a target of anticancer drug action in mammalian cells. N.C.I, monographs 4:61–71, 1987

  10. 10.

    Gewirtz DA: Does bulk damage to DNA explain the cytostatic and cytotoxic effects of topoisomerase II inhibitors? Biochem Pharm 42:2253–2258, 1991

  11. 11.

    Nguyen CH, Lhoste JM, Lavelle F, Bissery MC, Bisagni E: Synthesis and antitumor activity of l-[[dialkylamino) alkyl] amino]-4-methyl-5H-pyrido[4,3-b]benzo-[e]-and benzo[g])indoles. A new class of antineoplastic agents. J Med Chem 33:1519–1528, 1990

  12. 12.

    Nguyen CH, Lavelle F, Riou JF, Bissery MC, Huel C, Bisagni E: Further SAR in the new antitumor 1-amino-substitutedγ-carbolines and 5H-benzo[e]pyrido[4,3-b] indoles series. Anti-Cancer Drug Design 7:235–251, 1992

  13. 13.

    Lavelle F, Nguyen CH, Bissery MC, Riou JF, Bisagni E: Structure-activity relationships in the pyrido-benzo-indole series, a new class of antitumor agents. (Abstract) Proc Am Assoc Cancer Res 31:417, 1990

  14. 14.

    Riou JF, Fossé P, Bissery MC, Larsen AK, Nguyen CH, Grondard L, Saucier JM, Bisagni E, Lavelle F: RP 60475 and derivatives, a new class of antitumor agents inhibiting both topoisomerase I and II activities. (Abstract) Proc Am Assoc Cancer Res 33:437, 1992

  15. 15.

    Poddevin B, Riou JF, Lavelle F, Pommier Y: Dual topoisomerase I and II inhibition by RP 60475, an intercalating agent in early clinical trial. (Abstract) Proc Am Assoc Cancer Res 33:437, 1992

  16. 16.

    Bissery MC, Nguyen CH, Bisagni E and Lavelle F: Preclinical evaluation of RP 60475, a pyrido-benzo-indole antitumor agent. (Abstract) Proc Am Assoc Cancer Res 31:417, 1990

  17. 17.

    LoRusso P, Wozniak AJ, Polin L, Capps D, Leopold WR, Werbel LM, Biernat L, Dan ME, Corbett TH: Antitumor efficacy of PD115934 (NSC 366140) against solid tumors of mice. Cancer Res 50:4900–4905, 1990

  18. 18.

    Corbett TH, Griswold DP Jr., Roberts BJ, Peckham JC, Schabel FM Jr: Evaluation of single agents and combinations of chemotherapeutic agents in mouse colon carcinomas. Cancer 40:2660–2680, 1977

  19. 19.

    Corbett TH, Roberts BJ, Leopold WR, Peckham JC, Wilkoff LJ, Griswold DP Jr., Schabel FM Jr: Induction and chemotherapeutic response of two transplantable ductal adenocarcinomas of the pancreas in C57BL/6 mice. Cancer Res 44:717–726, 1984

  20. 20.

    Corbett TH, Griswold DP Jr, Roberts BJ, Peckham JC and Schabel FM Jr: Biology and therapeutic response of a mouse mammary adenocarcinoma (16/C) and its potential as a model for surgical adjuvant chemotherapy. Cancer Treat Rep 62:1471–1488, 1978

  21. 21.

    Glasgow LA, Crane JL Jr., Kern ER: Antitumor activity of interferon against murine osteogenic sarcoma cellsin vitro. J Natl Cancer Inst 60:659–666, 1978

  22. 22.

    Mayo JG: Biologic characterization of the subcutaneously implanted Lewis lung tumor. Cancer Chemother Rep, part 2, 3:325–330, 1972

  23. 23.

    Geran RI, Greenberg NH, Macdonald MM, Schumacher AM, Abbott BJ: Protocols for screening chemical agents and natural products against animal tumors and other biological systems (third edition). Cancer Chemother Rep, part. 3:1–103, 1972

  24. 24.

    Schabel FM Jr., Skipper HE, Trader MW, Laster WR Jr, Griswold DP Jr and Corbett TH: Establishment of crossresistance profiles for new agents. Cancer Treat Rep 67:905–922, 1983

  25. 25.

    Corbett TH, Roberts BJ, Trader MW, Laster WR Jr, Griswold DP Jr, Schabel FM Jr: Response of transplantable tumors of mice to anthracenedione derivatives alone and in combination with clinically useful agents. Cancer Treat Rep 66:1187–1200, 1982

  26. 26.

    Corbett TH, Leopold WR, Dykes DJ, Roberts BJ, Griswold DP Jr., Schabel FM Jr: Toxicity and anticancer activity of a new triazine antifolate (NSC 127755). Cancer Res 42:1707–1715, 1982

  27. 27.

    Bissery MC, André S, Renard A, Montay G, Bayssas M, Lavelle F: Preclinical pharmacology and toxicology of RP 60475, a new benzopyrido-indole. (Abstract) Annals of Oncology, Supplement 1, 3:94, 1992

  28. 28.

    Strauss G, Pagani O, Sessa C, Lund B, Cavalli F, Hansen HH. A phase I study of intoplicine (RP 60475F, NSC D 645008) administered on a daily × 5 schedule. (Abstract) Proc Am Assoc Cancer Res 34:231, 1993

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Correspondence to Marie-Christine Bissery.

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Bissery, M., Nguyen, C.H., Bisagni, E. et al. Antitumor activity of intoplicine (RP 60475, NSC 645008), a new benzo-pyrido-indole: evaluation against solid tumors and leukemias in mice. Invest New Drugs 11, 263–277 (1993). https://doi.org/10.1007/BF00874425

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Key words

  • RP 60475
  • intoplicine
  • transplantable tumors of mice
  • antitumor activity
  • DNA topoisomerase inhibitor