title: Cellular basis of antiproliferative and antitumor activity of the novel camptothecin derivative, gimatecan, in bladder carcinoma models.
abstract: To investigate the cellular/molecular basis of the activity of a novel lipophilic camptothecin, gimatecan (ST1481), against slowly proliferating cells, we performed a comparative study of topotecan and gimatecan in human bladder cancer models (HT1376 and MCR). Gimatecan was significantly more effective than topotecan in inhibiting the growth of HT1376 tumor, thus reflecting antiproliferative potency. In both HT1376 and MCR cells, gimatecan caused a persistent S-phase arrest, indicating an efficient DNA damage checkpoint. This response was consistent with a cytostatic effect, because no evidence of apoptosis was detected. In contrast to gimatecan, topotecan at equitoxic concentrations caused an early and persistent downregulation of topoisomerase I. Modulation of protein level could not be solely ascribed to the proteasome-mediated degradation of the enzyme because the proteasome inhibitor PS341 sensitized MCR but not HT1376 cells to camptothecins, suggesting alternative mechanisms of drug-induced topoisomerase I downregulation. Indeed, the two camptothecins caused a differential inhibition of topoisomerase I transcription, which is more marked in topotecan-treated cells. The HT1376 model was more sensitive to this immediate decrease of mRNA level. Our data document a marked antitumor activity of gimatecan against a bladder carcinoma model. A limited downregulation of topoisomerase I by gimatecan provides additional insights into the cellular basis of drug potency.
authors.affiliation: Istituto Oncologico Romagnolo, Forlì, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ulivi
authors.forename: Wainer
authors.initials: W
authors.lastname: Zoli
authors.forename: Francesco
authors.initials: F
authors.lastname: Fabbri
authors.forename: Giovanni
authors.initials: G
authors.lastname: Brigliadori
authors.forename: Luca
authors.initials: L
authors.lastname: Ricotti
authors.forename: Anna
authors.initials: A
authors.lastname: Tesei
authors.forename: Marco
authors.initials: M
authors.lastname: Rosetti
authors.forename: Michelandrea
authors.initials: M
authors.lastname: De Cesare
authors.forename: Giovanni L
authors.initials: GL
authors.lastname: Beretta
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Corna
authors.forename: Rosanna
authors.initials: R
authors.lastname: Supino
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011480:Protease Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D012333:RNA, Messenger; C433984:ST 1481; D059004:Topoisomerase I Inhibitors; D000069286:Bortezomib; D019772:Topotecan; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin