Gimatecan, a novel camptothecin with a promising preclinical profile.

Abstract

The realization that position 7 of camptothecin allows several options in chemical manipulation of the drug has stimulated a systematic investigation of a variety of substituents in this position. These efforts resulted in the identification of a novel series of 7-oxyiminomethyl derivatives. Among compounds of this series we have selected a promising lipophilic derivative, gimatecan, for further development. The relevant features of gimatecan are: (i) marked cytotoxic potency, likely related to multiple factors, including a potent inhibition of topoisomerase I, a persistent stabilization of the cleavable complex, an increased intracellular accumulation and a peculiar subcellular localization; (ii) lack of recognition by known resistance-related transport systems; (iii) increased lactone stability and favorable pharmacokinetics; (iv) good oral bioavailability; and (v) an impressive antitumor efficacy in a large panel of human tumor xenografts, with various treatment schedules. Phase I clinical studies with oral administration support the preclinical results of the novel camptothecin. Using different schedules and dosing durations, gimatecan exhibited an acceptable toxicity profile, with myelotoxicity being the dose-limiting toxic effect. An appreciable number of tumor responses was achieved and favorable pharmacokinetics with a very long terminal half-life was observed. The clinical development of gimatecan is currently ongoing, with phase II studies in diverse tumor types (colon, lung, breast carcinoma and pediatric tumors).

• Authors: Graziella Pratesi, Giovanni L Beretta, Franco Zunino
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 15 Issue 6 Pg. 545-52 (Jul 2004) ISSN: 0959-4973 [Print] England
• PMID: 15205595 (Publication Type: Journal Article, Review)

Chemical References

• ST 1481
• Camptothecin

Topics

• Administration, Oral
• Animals
• Camptothecin (administration & dosage, analogs & derivatives, pharmacokinetics, therapeutic use)
• Clinical Trials, Phase I as Topic
• Clinical Trials, Phase II as Topic
• Drug Evaluation, Preclinical (methods)
• Drug Screening Assays, Antitumor (methods)
• Humans
• Multicenter Studies as Topic