IN-VIVO ANTITUMOR-ACTIVITY OF 2 NEW 7-SUBSTITUTED WATER-SOLUBLE CAMPTOTHECIN ANALOGS

The development of camptothecin-like compounds as inhibitors of topois omerase I for the treatment of resistant tumors has generated clinical excitement in this new class of drugs. We have developed two novel wa ter-soluble camptothecin analogues which are specific inhibitors of to poisomerase I and are potent cytotoxins with significant antitumor act ivity. We added water-solubilizing groups off position 7 in the B ring of either 10,11-ethylenedioxy- or 10,11-methylenedioxy-20(S)-camptoth ecin. These water-soluble camptothecin analogues were demonstrated to he nanamolar inhibitors of the topoisomerase I enzyme in the cleavable complex assay. The compounds, GI147211 ethylene)-10,11-ethylenedioxy- 20(S)-camptothecin], and GI149893 thylene)-10,11-methylenedioxy-20(S)- camptothecin], were compared to topotecan, a known water-soluble inhib itor of topoisomerase I. Both GI compounds were found to be slightly m ore potent than topotecan as inhibitors of topoisomerase I in the clea vable complex assay and were 1.5-2 times more soluble. Tumor cell cyto toxicity assays using 5 separate cell lines demonstrated that both GI compounds were 5-10 times more potent than topotecan, although by comp arison all three topoisomerase I inhibitors were unaffected by the mul tidrug resistance P-glycoprotein. The antitumor activity of all three topoisomerase I inhibitors was compared concomitantly in two human col on xenograft models. In both models, GI147211 and GI149893 were able t o induce regression of established HT-29 and SW-48 colon tumors by as much as 60%. The antitumor activity of both compounds were also demons trated in the MX-1 and PC-3 xenografts. Microscopic examination of sel ected tissues indicated that drug-induced toxicity was primarily Limit ed to the gastrointestinal tract and was comparable among the three co mpounds. Further clinical development of this class of compounds is on going.