title: In vitro and in vivo antitumour effects of novel, orally active bile acid-conjugated platinum complexes on rat hepatoma.
abstract: (NH3)2Pt(triacid) and (PPh3)2Pt(dehydrocholate)2 are novel bile acid-conjugated platinum complexes administered by oral route. The aims of the present study were to evaluate their in vitro cytotoxic activities on rat hepatoma cell line N1-S1, the in vivo antitumour effects in a syngeneic and orthotopic rat hepatoma model and the drug-related toxicities. Cisplatin, carboplatin and mitoxantrone were used as control drugs. In vitro experiments showed a concentration- and time-dependent antiproliferative activity of bile-conjugated platinum complexes. (NH3)2Pt(triacid) had similar effects on cell growth of cisplatin and carboplatin (e.g. at 48 h, IC50 0.7+/-0.05 microM vs. 0.63+/-0.28 microM and 1.1+/-0.3 microM, respectively; mean+/-S.D.). (NH3)2Pt(triacid) was able to inhibit tumour growth in a dose-dependent extent, reaching the maximum inhibitory effect at the 80 mg/kg dose (1.95+/-0.5 g vs. 13.85+/-3.9 g of control tumour weight). By contrast, despite the promising in vitro antiproliferative activity, (PPh3)2Pt(dehydrocholate)2 showed no significant in vivo antitumour effect. The toxicity profile of (NH3)2Pt(triacid) resulted favourable with minimal loss of weight and no gastrointestinal or neurological symptoms. Instead, (PPh3)2Pt(dehydrocholate)2 showed dose-dependent signs of severe weight loss and neurological alterations. In conclusion (NH3)2Pt(triacid) is a tolerable and active platinum derivative endowed by a preclinical antitumour activity by oral route.
authors.affiliation: Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, Via Roma, 55 I-56126 Pisa, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Barbara
authors.forename: Paola
authors.initials: P
authors.lastname: Orlandi
authors.forename: Guido
authors.initials: G
authors.lastname: Bocci
authors.forename: Anna
authors.initials: A
authors.lastname: Fioravanti
authors.forename: Antonello
authors.initials: A
authors.lastname: Di Paolo
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Natale
authors.forename: Mario
authors.initials: M
authors.lastname: Del Tacca
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001647:Bile Acids and Salts / Q000737:chemistry; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010984:Platinum / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D001647:Bile Acids and Salts; D009944:Organoplatinum Compounds; C513016:cis-(di(dehydrocholanoate)-bis(triphenylphosphine)-platinum(II)); D010984:Platinum