Homocamptothecin, an E-ring-modified camptothecin, exerts more potent antiproliferative activity than other topoisomerase I inhibitors in human coloncancers obtained from surgery and maintained in vitro under histotypical culture conditions

Topoisomerase I (Topo I) is overexpressed in cancer colon tissues compared with normal colon tissues. Several anti-Topo I inhibitors are already succe ssfully used in the clinic. We illustrate here the antiproliferative activi ty of a new class of Topo I inhibitors, i.e., E-ring-modified camptothecins with enhanced lactone stability (L. Lesueur-Ginot et at, Cancer Res., 59:2 939-2943, 1999), Forty-three human colon cancers were obtained from surgica l 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 clinical ly active topoisomerase II (Topo II) inhibitors, Adriamycin and etoposide, which are not active for colon cancers; and three Topo I inhibitors, campto thecin (CPT) and two clinically active compounds (especially for colon canc ers), i.e., topotecan and the active metabolite of irinothecan, SN-38, We t hen compared the antiproliferative activity of CPT, topotecan, and SN-38 ag ainst those of two investigational E-ring-modified camptothecins, i.e., BN8 0245 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 tha n the two Topo II inhibitors, Le., Adriamycin and etoposide, with SN-38 bei ng the most efficient. The two investigational compounds BN80245 and BN8091 5 exerted higher antiproliferative activity than the three anti-Topo I refe rence compounds, with the highest activity observed for BN80915.