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In vivo antitumor activity of two new seven-substituted water-soluble camptothecin analogues.
Cancer Res. 1995 Feb 01; 55(3):603-9.CR

Abstract

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.

Authors+Show Affiliations

Department of Pharmacology, Glaxo Research Institute, Research Triangle Park, North Carolina 27709.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

7834631

Citation

Emerson, D L., et al. "In Vivo Antitumor Activity of Two New Seven-substituted Water-soluble Camptothecin Analogues." Cancer Research, vol. 55, no. 3, 1995, pp. 603-9.
Emerson DL, Besterman JM, Brown HR, et al. In vivo antitumor activity of two new seven-substituted water-soluble camptothecin analogues. Cancer Res. 1995;55(3):603-9.
Emerson, D. L., Besterman, J. M., Brown, H. R., Evans, M. G., Leitner, P. P., Luzzio, M. J., Shaffer, J. E., Sternbach, D. D., Uehling, D., & Vuong, A. (1995). In vivo antitumor activity of two new seven-substituted water-soluble camptothecin analogues. Cancer Research, 55(3), 603-9.
Emerson DL, et al. In Vivo Antitumor Activity of Two New Seven-substituted Water-soluble Camptothecin Analogues. Cancer Res. 1995 Feb 1;55(3):603-9. PubMed PMID: 7834631.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vivo antitumor activity of two new seven-substituted water-soluble camptothecin analogues. AU - Emerson,D L, AU - Besterman,J M, AU - Brown,H R, AU - Evans,M G, AU - Leitner,P P, AU - Luzzio,M J, AU - Shaffer,J E, AU - Sternbach,D D, AU - Uehling,D, AU - Vuong,A, PY - 1995/2/1/pubmed PY - 1995/2/1/medline PY - 1995/2/1/entrez SP - 603 EP - 9 JF - Cancer research JO - Cancer Res. VL - 55 IS - 3 N2 - 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. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/7834631/In_vivo_antitumor_activity_of_two_new_seven_substituted_water_soluble_camptothecin_analogues_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=7834631 DB - PRIME DP - Unbound Medicine ER -