This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ciomei, M. Articles by Pesenti, E. Search for Related Content PubMed PubMed Citation Articles by Ciomei, M. Articles by Pesenti, E.

Antitumor Efficacy of Edotecarin as a Single Agent and in Combination with Chemotherapy Agents in a Xenograft Model

Authors' Affiliation: Department of Biology, Drug Discovery Oncology, Nerviano Medical Sciences, Nerviano, Milan, Italy

Requests for reprints: Marina Ciomei, Biology Department, Nerviano Medical Sciences, Building 75, A2 13, viale Pasteur, 10, 20014 Nerviano, Milan, Italy. Phone: 39-0331-581134; Fax: 39-0331-581374; E-mail: marina.ciomei{at}nervianoms.com.

The novel indolocarbazole edotecarin (J-107088, formerly ED-749) differs from other topoisomerase I inhibitors both pharmacokinetically and pharmacodynamically. In vitro, it is more potent than camptothecins and has a variable cytotoxic activity in 31 different human cancer cell lines. Edotecarin also possesses greater than additive inhibitory effects on cell proliferation when used in combination with other agents tested in vitro against various cancer cell lines. The present in vivo studies were done to extend the in vitro findings to characterize the antitumor effects of edotecarin when used either alone or in combination with other agents (i.e., 5-fluorouracil, irinotecan, cisplatin, oxaliplatin, and SU11248) in the HCT-116 human colon cancer xenograft model. Treatment effects were based on the delay in onset of an exponential growth of tumors in drug-treated versus vehicle control-treated groups. In all studies, edotecarin was active both as a single agent and in combination with other agents. Combination therapy resulted in greater than additive effects, the extent of which depended on the specific dosage regimen. Toxicity in these experiments was minimal. Of all 359 treated mice, the six that died of toxicity were in the high-dose edotecarin/oxaliplatin group. The results suggest that edotecarin may serve as effective chemotherapy of colon cancer when used as a single agent, in combination with standard regimens and other topoisomerase inhibitors or with novel agents, such as the multitargeted tyrosine kinase inhibitor SU11248.