Regular Article

British Journal of Cancer (2000) 83, 1516–1524. doi:10.1054/bjoc.2000.1428 www.bjcancer.com
Published online 14 November 2000

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

A Kruczynski1,4, C Etiévant1, D Perrin1, T Imbert2, F Colpaert3 and B T Hill1

  1. 1Division of Experimental Cancer Research, 17 avenue Jean Moulin, Castres, Cedex 06, 81106, France
  2. 2Division of Medicinal Chemistry III, 17 avenue Jean Moulin, Castres, Cedex 06, 81106, France
  3. 3Research Centre Directorate, 17 avenue Jean Moulin, Castres, Cedex 06, 81106, France
  4. 4Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, Castres, Cedex 06, 81106, France

Received 29 March 2000; Revised 21 June 2000; Accepted 23 June 2000.

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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

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