Low in vivo toxicity of a novel cisplatin-ursodeoxycholic derivative (Bamet-UD2) with enhanced cytostatic activity versus liver tumors

Citation
Mf. Dominguez et al., Low in vivo toxicity of a novel cisplatin-ursodeoxycholic derivative (Bamet-UD2) with enhanced cytostatic activity versus liver tumors, J PHARM EXP, 297(3), 2001, pp. 1106-1112
Citations number
40
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
ISSN journal
00223565 → ACNP
Volume
297
Issue
3
Year of publication
2001
Pages
1106 - 1112
Database
ISI
SICI code
0022-3565(200106)297:3<1106:LIVTOA>2.0.ZU;2-O
Abstract
Cisplatin-bile acid derivatives belonging to the Bamet-family maintain both liver organotropism and cytostatic activity. "In vivo" toxicity and useful ness as chemotherapeutic agent versus liver tumors of a novel drug, Bamet-U D2 [cis-diamminechlorocholylglycinate platinum (II)], with enhanced "in vit ro" cytostatic activity was investigated. Using orthotopically implanted mo use Hepa 1-6 hepatoma in the liver of Nude mice, the antitumor effect of Ba met-UD2 was compared with that of a previously characterized compound of th is family, Bamet-R2 [cis-diamminebis-ursodeoxycholate platinum(II)], and ci splatin. Life span was significantly prolonged in mice treated with both Ba mets (Bamet-UD2 > Bamet-R2), compared with animals receiving saline or cisp latin. All these drugs inhibit tumor growth (Bamet-UD2 = cisplatin > Bamet- R2), However, toxicity-related deaths only occurred under cisplatin treatme nt. Using rats maintained in metabolic cages, organ-specific toxicity and d rug accumulation in tissues were investigated. The amount of both Bamets in the liver was severalfold higher than that of cisplatin, By contrast, a si gnificantly higher amount of cisplatin in kidney and nerve was found. In lu ng, heart, muscle, brain, and bone marrow the amount of drug was small and also significantly lower in animals receiving Bamets. Signs of neurotoxicit y (altered nerve conduction velocity), nephrotoxicity (increased serum urea and creatinine concentrations and decreased creatinine clearance), and bon e marrow toxicity (decreased platelet and white blood counts) in animals tr eated with cisplatin but not with the Bamets were found. These results indi cate that, owing to strong antitumor activity together with absence of side effects, Bamet-UD2 may be useful in the treatment of liver tumors.