Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2000 Nov 22;83(11):1516–1524. doi: 10.1054/bjoc.2000.1428

Preclinical antitumour activity of F 11782, a novel dual catalytic inhibitor of topoisomerases

A Kruczynski 1,4, C Etiévant 1, D Perrin 1, T Imbert 2, F Colpaert 3, B T Hill 1
PMCID: PMC2363411  PMID: 11076662

Abstract

F 11782 is a novel inhibitor of topoisomerases I and II, with an original mechanism of action (Perrin et al, 2000). This study, aimed to define its anticancer efficacy against a series of murine and human tumour models, has provided evidence of major antitumour activity for F 11782. This was demonstrated as a high level of activity against the P388 leukaemia, as reflected by increased survival of 143–457%, when administered i.p., p.o. or i.v. as single or multiple doses, and proved consistently superior to etoposide or camptothecin tested concurrently. Single or multiple i.p. doses of F 11782 also proved highly active against the s.c. grafted B16 melanoma, significantly increasing survival (P < 0.001) and inhibiting tumour growth (T/C of 0.3%), again superior to etoposide tested concurrently. Furthermore, F 11782 inhibited the number of pulmonary metastatic foci of the B16F10 melanoma by 99%. In human tumour xenograft studies, multiple i.p. doses of F 11782 resulted in major inhibitory activity against MX-1 (breast) tumours (T/C of 0.1%), as well as causing definite tumour regressions, whereas none resulted from similar experimental treatments with etoposide. Significant activity was also recorded with F 11782 against the relatively refractory LX-1 (lung) xenografts, with an optimal T/C value of 19%. It was notable that the antitumour activity of F 11782 was consistently demonstrated over a wide range of 2–6 dose levels, providing evidence of its good overall tolerance. In conclusion, these results emphasize the preclinical interest of this novel molecule and support its further preclinical development. © 2000 Cancer Research Campaign http://www.bjcancer.com

Keywords: in vivo cancer chemotherapy, dual topoisomerase inhibitor

Full Text

The Full Text of this article is available as a PDF (96.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bissery M. C., Guénard D., Guéritte-Voegelein F., Lavelle F. Experimental antitumor activity of taxotere (RP 56976, NSC 628503), a taxol analogue. Cancer Res. 1991 Sep 15;51(18):4845–4852. [PubMed] [Google Scholar]
  2. Froelich-Ammon S. J., Osheroff N. Topoisomerase poisons: harnessing the dark side of enzyme mechanism. J Biol Chem. 1995 Sep 15;270(37):21429–21432. doi: 10.1074/jbc.270.37.21429. [DOI] [PubMed] [Google Scholar]
  3. Gatto B., Capranico G., Palumbo M. Drugs acting on DNA topoisomerases: recent advances and future perspectives. Curr Pharm Des. 1999 Mar;5(3):195–215. [PubMed] [Google Scholar]
  4. Hendriks H. R., Langdon S., Berger D. P., Breistøl K., Fiebig H. H., Fodstad O., Schwartsmann G. Comparative antitumour activity of vinblastine-isoleucinate and related vinca alkaloids in human tumour xenografts. Eur J Cancer. 1992;28A(4-5):767–773. doi: 10.1016/0959-8049(92)90112-f. [DOI] [PubMed] [Google Scholar]
  5. Husain I., Mohler J. L., Seigler H. F., Besterman J. M. Elevation of topoisomerase I messenger RNA, protein, and catalytic activity in human tumors: demonstration of tumor-type specificity and implications for cancer chemotherapy. Cancer Res. 1994 Jan 15;54(2):539–546. [PubMed] [Google Scholar]
  6. Ishida R., Hamatake M., Wasserman R. A., Nitiss J. L., Wang J. C., Andoh T. DNA topoisomerase II is the molecular target of bisdioxopiperazine derivatives ICRF-159 and ICRF-193 in Saccharomyces cerevisiae. Cancer Res. 1995 Jun 1;55(11):2299–2303. [PubMed] [Google Scholar]
  7. Khélifa T., Beck W. T. Merbarone, a catalytic inhibitor of DNA topoisomerase II, induces apoptosis in CEM cells through activation of ICE/CED-3-like protease. Mol Pharmacol. 1999 Mar;55(3):548–556. [PubMed] [Google Scholar]
  8. Kruczynski A., Colpaert F., Tarayre J. P., Mouillard P., Fahy J., Hill B. T. Preclinical in vivo antitumor activity of vinflunine, a novel fluorinated Vinca alkaloid. Cancer Chemother Pharmacol. 1998;41(6):437–447. doi: 10.1007/s002800050764. [DOI] [PubMed] [Google Scholar]
  9. Langdon S. P., Hendriks H. R., Braakhuis B. J., Pratesi G., Berger D. P., Fodstad O., Fiebig H. H., Boven E. Preclinical phase II studies in human tumor xenografts: a European multicenter follow-up study. Ann Oncol. 1994 May;5(5):415–422. doi: 10.1093/oxfordjournals.annonc.a058872. [DOI] [PubMed] [Google Scholar]
  10. Ovejera A. A., Houchens D. P. Human tumor xenografts in athymic nude mice as a preclinical screen for anticancer agents. Semin Oncol. 1981 Dec;8(4):386–393. [PubMed] [Google Scholar]
  11. Perrin D., van Hille B., Barret J. M., Kruczynski A., Etiévant C., Imbert T., Hill B. T. F 11782, a novel epipodophylloid non-intercalating dual catalytic inhibitor of topoisomerases I and II with an original mechanism of action. Biochem Pharmacol. 2000 Apr 1;59(7):807–819. doi: 10.1016/s0006-2952(99)00382-2. [DOI] [PubMed] [Google Scholar]
  12. Pratesi G., De Cesare M., Zunino F. Efficacy of lonidamine combined with different DNA-damaging agents in the treatment of the MX-1 tumor xenograft. Cancer Chemother Pharmacol. 1996;38(2):123–128. doi: 10.1007/s002800050459. [DOI] [PubMed] [Google Scholar]
  13. Riou J. F., Helissey P., Grondard L., Giorgi-Renault S. Inhibition of eukaryotic DNA topoisomerase I and II activities by indoloquinolinedione derivatives. Mol Pharmacol. 1991 Nov;40(5):699–706. [PubMed] [Google Scholar]
  14. Utsugi T., Shibata J., Sugimoto Y., Aoyagi K., Wierzba K., Kobunai T., Terada T., Oh-hara T., Tsuruo T., Yamada Y. Antitumor activity of a novel podophyllotoxin derivative (TOP-53) against lung cancer and lung metastatic cancer. Cancer Res. 1996 Jun 15;56(12):2809–2814. [PubMed] [Google Scholar]
  15. Venditti J. M. Preclinical drug development: rationale and methods. Semin Oncol. 1981 Dec;8(4):349–361. [PubMed] [Google Scholar]
  16. Yamashita Y., Kawada S., Fujii N., Nakano H. Induction of mammalian DNA topoisomerase I and II mediated DNA cleavage by saintopin, a new antitumor agent from fungus. Biochemistry. 1991 Jun 18;30(24):5838–5845. doi: 10.1021/bi00238a005. [DOI] [PubMed] [Google Scholar]
  17. van der Zee A. G., Hollema H., de Jong S., Boonstra H., Gouw A., Willemse P. H., Zijlstra J. G., de Vries E. G. P-glycoprotein expression and DNA topoisomerase I and II activity in benign tumors of the ovary and in malignant tumors of the ovary, before and after platinum/cyclophosphamide chemotherapy. Cancer Res. 1991 Nov 1;51(21):5915–5920. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES