The development of
camptothecin-like compounds as inhibitors of
topoisomerase I for the treatment of resistant
tumors has generated clinical excitement in this new class of drugs. We have developed two novel water-soluble
camptothecin analogues which are specific inhibitors of
topoisomerase I and are potent
cytotoxins with significant antitumor activity. We added water-solubilizing groups off position 7 in the B ring of either 10,11-ethylenedioxy- or 10,11-methylenedioxy-20(S)-camptothecin. These water-soluble
camptothecin analogues were demonstrated to be nanamolar inhibitors of the
topoisomerase I enzyme in the cleavable complex assay. The compounds,
GI147211 [7-(4-methylpiperazinomethylene)-10,11-ethylenedioxy-20(S)-camp tot hecin], and
GI149893 [7-(4-methylpiperazinomethylene)-10,11-methylenedioxy-20(S)-cam pto thecin], were compared to
topotecan, a known water-soluble inhibitor of
topoisomerase I. Both GI compounds were found to be slightly more potent than
topotecan as inhibitors of
topoisomerase I in the cleavable complex assay and were 1.5-2 times more soluble.
Tumor cell cytotoxicity assays using 5 separate cell lines demonstrated that both GI compounds were 5-10 times more potent than
topotecan, although by comparison all three
topoisomerase I inhibitors were unaffected by the multidrug resistance
P-glycoprotein. The antitumor activity of all three
topoisomerase I inhibitors was compared concomitantly in two human colon xenograft models. In both models,
GI147211 and
GI149893 were able to induce regression of established HT-29 and SW-48 colon
tumors by as much as 60%. The antitumor activity of both compounds were also demonstrated in the MX-1 and PC-3 xenografts. Microscopic examination of selected tissues indicated that
drug-induced toxicity was primarily limited to the gastrointestinal tract and was comparable among the three compounds. Further clinical development of this class of compounds is ongoing.