title: 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.affiliation: Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy. graziella.pratesi@istitutotumori.mi.it
authors.forename: Graziella
authors.initials: G
authors.lastname: Pratesi
authors.forename: Giovanni L
authors.initials: GL
authors.lastname: Beretta
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D015337:Multicenter Studies as Topic
chemical_list: C433984:ST 1481; D002166:Camptothecin