title: Efficacy of ST1968 (namitecan) on a topotecan-resistant squamous cell carcinoma.
abstract: ST1968 (namitecan), a novel 7-modified hydrophilic camptothecin, was found to be effective against tumor models relatively resistant to topotecan and irinotecan. Based on this observation, this study was designed to investigate the cellular and antitumor effects of ST1968 in a subline of A431, squamous cell carcinoma, selected for resistance to topotecan (A431/TPT). This model was characterized by a slow growth rate, associated with downregulation of EGFR and topoisomerase I. In contrast to other camptothecins (SN38 and gimatecan), ST1968 was able to overcome almost completely the resistance at cellular level. The cellular pharmacokinetics indicated a comparable accumulation and retention of ST1968 in sensitive and resistant cells, in spite of expression of the efflux transporter, P-glycoprotein, in resistant cells. The uptake and retention of topotecan were dramatically reduced in both tumor cell lines, but more evident in the resistant one. In contrast to topotecan, ST1968 retained an outstanding efficacy in vivo against the resistant tumor (A431/TPT). The results are consistent with the interpretation that ST1968 was able to overcome the most relevant mechanisms associated with the development of topotecan resistance (i.e., slow proliferation and target downregulation) owing to its peculiar pharmacokinetic behaviour.
authors.affiliation: Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Zuco
authors.forename: Rosanna
authors.initials: R
authors.lastname: Supino
authors.forename: Enrica
authors.initials: E
authors.lastname: Favini
authors.forename: Monica
authors.initials: M
authors.lastname: Tortoreto
authors.forename: Raffaella
authors.initials: R
authors.lastname: Cincinelli
authors.forename: Anna Cleta
authors.initials: AC
authors.lastname: Croce
authors.forename: Federica
authors.initials: F
authors.lastname: Bucci
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D019772:Topotecan / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D019772:Topotecan; C531200:namitecan; D002166:Camptothecin