title: Biological properties of IDN5174, a new synthetic camptothecin with the open lactone ring.
abstract: A series of water-soluble camptothecins obtained by linking a spermidine moiety to the 21-position of the open form through an amidic bond have been tested for their biochemical and biological activities. Growth inhibition assay on the human non-small cell lung cancer carcinoma NCI-H460 cell line revealed that the camptothecin analogues were less potent than topotecan and SN38 after 1 hour of treatment. The potency increased after 72 hours of exposure, being similar to that of reference camptothecins. The analysis of topoisomerase I-mediated DNA cleavage using the purified enzyme indicated that the novel camptothecin analogues retained ability to poison topoisomerase I and displayed the same cleavage pattern of SN38. Persistence of the DNA cleavage was comparable with that of SN38. Stabilization of the cleavable complex was not the result of hydrolysis of the N-C bond between polyamine and the drug because no free camptothecin was recovered at the end of DNA cleavage in presence of IDN5174, the analogue selected for detailed studies. IDN5174 exhibited an antitumor activity comparable with that of topotecan and irinotecan against NCI-H460 tumor xenograft. The pharmacokinetics in mice showed a favorable disposition in tumor tissue with low amount of camptothecin detectable in plasma and tumor (around 5-10%), thus supporting the efficacy of intact IDN5174. In conclusion, we found that IDN5174 maintained the biological and antitumor properties, in spite of lack of the closed E ring. The available results support the interpretation that the polyamine linked at the 21-position may allow a favorable drug interaction in the ternary complex.
authors.affiliation: Department of Experimental Oncology and Laboratories, Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Giovanni L
authors.initials: GL
authors.lastname: Beretta
authors.forename: Giovanna
authors.initials: G
authors.lastname: Petrangolini
authors.forename: Michelandrea
authors.initials: M
authors.lastname: De Cesare
authors.forename: Graziella
authors.initials: G
authors.lastname: Pratesi
authors.forename: Paola
authors.initials: P
authors.lastname: Perego
authors.forename: Stella
authors.initials: S
authors.lastname: Tinelli
authors.forename: Monica
authors.initials: M
authors.lastname: Tortoreto
authors.forename: Massimo
authors.initials: M
authors.lastname: Zucchetti
authors.forename: Roberta
authors.initials: R
authors.lastname: Frapolli
authors.forename: Ezia
authors.initials: E
authors.lastname: Bello
authors.forename: Carla
authors.initials: C
authors.lastname: Manzotti
authors.forename: Gabriele
authors.initials: G
authors.lastname: Fontana
authors.forename: Ezio
authors.initials: E
authors.lastname: Bombardelli
authors.forename: Arturo
authors.initials: A
authors.lastname: Battaglia
authors.forename: Cristian
authors.initials: C
authors.lastname: Samorì
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D013095:Spermidine / Q000031:analogs & derivatives; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C515446:IDN5174; D007783:Lactones; D004264:DNA Topoisomerases, Type I; D013095:Spermidine; D002166:Camptothecin