title: IDN5109, a taxane with oral bioavailability and potent antitumor activity.
abstract: IDN5109 is a new taxane, derived from 14beta-hydroxy-10-deacetylbaccatin III, selected for its lack of cross-resistance in tumor cell lines expressing the multidrug resistant phenotype. Because, unlike paclitaxel, IDN5109 is a poor substrate for P-glycoprotein, we hypothesized that IDN5109 given p.o. could improve bioavailability compared with paclitaxel. Here, we studied the p.o. and i.v. pharmacokinetics of IDN5109 together with its antitumor activity. Using a high-performance liquid chromatography method, the bioavailability of IDN5109 was determined to be 48% after oral delivery. IDN5109 given p.o. was highly active against the two human ovarian carcinoma xenografts 1A9 and HOC18 (90-100% tumor regressions) and showed significant activity on the paclitaxel-resistant MNB-PTX1 xenograft (10% tumor regressions). The p.o. administration was as active as the i.v. route at doses reflecting the pharmacokinetic data. IDN5109 is the first taxane with good oral bioavailability and potent antitumor activity and represents a potential candidate for clinical investigation.
authors.affiliation: Department of Oncology, Laboratory of Biology and Treatment of Metastasis, Mario Negri Institute for Pharmacological Research, Bergamo, Italy. Nicoletti@irfmn.mnegri.it
authors.forename: M I
authors.initials: MI
authors.lastname: Nicoletti
authors.forename: T
authors.initials: T
authors.lastname: Colombo
authors.forename: C
authors.initials: C
authors.lastname: Rossi
authors.forename: C
authors.initials: C
authors.lastname: Monardo
authors.forename: S
authors.initials: S
authors.lastname: Stura
authors.forename: M
authors.initials: M
authors.lastname: Zucchetti
authors.forename: A
authors.initials: A
authors.lastname: Riva
authors.forename: P
authors.initials: P
authors.lastname: Morazzoni
authors.forename: M B
authors.initials: MB
authors.lastname: Donati
authors.forename: E
authors.initials: E
authors.lastname: Bombardelli
authors.forename: M
authors.initials: M
authors.lastname: D'Incalci
authors.forename: R
authors.initials: R
authors.lastname: Giavazzi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001682:Biological Availability; D001952:Bridged-Ring Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000031:analogs & derivatives*; D043823:Taxoids
chemical_list: D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D043823:Taxoids; C404743:IDN 5109; D017239:Paclitaxel