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Homocamptothecin, an E-Ring-modified Camptothecin, Exerts More Potent Antiproliferative Activity than Other Topoisomerase I Inhibitors in Human Colon Cancers Obtained from Surgery and Maintained in Vitro under Histotypical Culture Conditions¹

Département de Chirurgie, Centre Hospitalier Universitaire Brugmann, 1090 Brussels, Belgium [P. P., L. H., P. M. D. C.]; Laboratoire d’Histopathologie, Faculté de Médecine, Université Libre de Bruxelles, 1070 Brussels, Belgium [C. C., C. D., Y. B., R. K.]; Service de Médecine Interne, Institut Jules Bordet, 1000 Brussels, Belgium [L. G.]; Institut Henri Beaufour, 91966 Les Ulis, France [L. L-G., O. L., D. C. H. B.]; and Laboratoire de Pharmacologie, Institut de Pharmacie, Université Libre de Bruxelles, 1050 Brussels, Belgium [H. M.]

Topoisomerase I (Topo I) is overexpressed in cancer colon tissues compared with normal colon tissues. Several anti-Topo I inhibitors are already successfully used in the clinic. We illustrate here the antiproliferative activity of a new class of Topo I inhibitors, i.e., E-ring-modified camptothecins with enhanced lactone stability (L. Lesueur-Ginot et al., Cancer Res., 59: 2939–2943, 1999). Forty-three human colon cancers were obtained from surgical resection and maintained under organotypical culture conditions for 48 h. Cell proliferation was assessed in these ex vivo tumor tissue cultures by tritiated thymidine autoradiography. As a validation of the methodology, we first analyzed in our model the antiproliferative activity of two clinically active topoisomerase II (Topo II) inhibitors, Adriamycin and etoposide, which are not active for colon cancers; and three Topo I inhibitors, camptothecin (CPT) and two clinically active compounds (especially for colon cancers), i.e., topotecan and the active metabolite of irinothecan, SN-38. We then compared the antiproliferative activity of CPT, topotecan, and SN-38 against those of two investigational E-ring-modified camptothecins, i.e., BN80245 and BN80915. Three concentrations (1, 10, and 100 nM) were studied for each compound. The results indicate that the three Topo I inhibitors used as references, i.e., CPT, irinothecan, and SN-38, were much more active than the two Topo II inhibitors, i.e., Adriamycin and etoposide, with SN-38 being the most efficient. The two investigational compounds BN80245 and BN80915 exerted higher antiproliferative activity than the three anti-Topo I reference compounds, with the highest activity observed for BN80915.

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