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
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.