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

Cisplatin-bile acid derivatives belonging to the Bamet-family maintain both liver organotropism and cytostatic activity. "In vivo" toxicity and usefulness as chemotherapeutic agent versus liver tumors of a novel drug, Bamet-UD2 [cis-diamminechlorocholylglycinate platinum (II)], with enhanced "in vitro" cytostatic activity was investigated. Using orthotopically implanted mouse Hepa 1-6 hepatoma in the liver of Nude mice, the antitumor effect of Bamet-UD2 was compared with that of a previously characterized compound of this family, Bamet-R2 [cis-diamminebis-ursodeoxycholate platinum(II)], and cisplatin. Life span was significantly prolonged in mice treated with both Bamets (Bamet-UD2 > Bamet-R2), compared with animals receiving saline or cisplatin. All these drugs inhibit tumor growth (Bamet-UD2 = cisplatin > Bamet-R2). However, toxicity-related deaths only occurred under cisplatin treatment. Using rats maintained in metabolic cages, organ-specific toxicity and drug accumulation in tissues were investigated. The amount of both Bamets in the liver was severalfold higher than that of cisplatin. By contrast, a significantly higher amount of cisplatin in kidney and nerve was found. In lung, heart, muscle, brain, and bone marrow the amount of drug was small and also significantly lower in animals receiving Bamets. Signs of neurotoxicity (altered nerve conduction velocity), nephrotoxicity (increased serum urea and creatinine concentrations and decreased creatinine clearance), and bone marrow toxicity (decreased platelet and white blood counts) in animals treated with cisplatin but not with the Bamets were found. These results indicate that, owing to strong antitumor activity together with absence of side effects, Bamet-UD2 may be useful in the treatment of liver tumors.

Estudio del Bamet-U2, un nuevo citostático no nefrotóxico derivado del cisplatino / Preclinical study of Bamet-U2, a novel non-nephrotoxic cisplatin derivative

El objetivo del trabajo fue investigar si, aprovechando el hepatotropismo de los ácidos biliares, se puede dotar a citostáticos, como el cisplatino, de vectorialidad hepatobiliar, reduciendo así su nefrotoxicidad. Por unión del cisplatino al ácido ursodesoxicólico se obtuvo Bamet-U2, que mantiene la capacidad de unirse al ADN, lo que reduce la intercalación del bromuro de etidio. La viabilidad celular de líneas derivadas de adenocarcinoma de colon y hepatoma humano, hepatoma de rata, hepatoma, leucemia y sarcoma de ratón no se afectó por incubación con ácido ursodesoxicólico, pero sí con cisplatino o Bamet-U2. El tratamiento con Bamet-U2, pero no con cisplatino, alargó la supervivencia media de los ratones atímicos implantados ortotópicamente en el hígado con células de hepatoma de ratón. El tratamiento con cisplatino, pero no con Bamet-U2, indujo una marcada reducción del aclaramiento de creatinina en ratas mantenidas en jaulas metabólicas. En conclusión, el Bamet-U2 mantiene los efectos citostáticos in vitro y antitumorales in vivo propios del cisplatino, pero reduce considerablemente sus efectos nefrotóxicos, lo que condicionó que el efecto terapéutico global que se consiguió en ratones con tumores hepáticos fuese mejor para el Bamet-U2 que para el cisplatino (AU)

Relationship between DNA-reactivity and cytostatic effect of two novel bile acid-platinum derivatives, Bamet-UD2 and Bamet-D3.

BACKGROUND AND AIMS: Several platinum(II)-bile acid derivatives, named Bamets, have been previously synthesized. Their ability to interact with DNA, their cytostatic activity and their liver organotropic properties have been characterized. Two new compounds of this family, with particular structural properties, have been developed. Bamet-UD2 was formed by two ursodeoxycholic acid moieties bound by the carboxylate groups to cisplatin. In contrast, in Bamet-D3, glycine and a polyamine were used as tandem spacer elements to separate a cholic acid moiety from the platinum(II) atom. The aim of this work was to evaluate how these changes affect the ability of these compounds to interact with DNA and reduce tumour cell growth. MATERIALS AND METHODS: Drug reactivity with DNA was determined by changes in the electrophoretic mobility of the pUC18 plasmid test and by the ethidium bromide (EthBr) displacement assay. Cytostatic activity was measured against two mouse-derived cell lines from lymphocytic leukemia (L1210) and sarcoma (S-180-II). RESULTS: Bamet-UD2, and more markedly Bamet-D3, induced changes in the electrophoretic mobility of pUC18, suggesting the formation of DNA-drug interactions. Bamet-UD2 displaced EthBr from its binding to DNA. This effect was stronger in the case of Bamet-D3. Scatchard plots revealed that pre-incubation with both Bamet-UD2 and Bamet-D3 decreased the number of DNA sites available and their ability to bind EthBr. In spite of the enhanced DNA-reactivity of Bamet-D3, its ability to reduce tumour cell growth was much weaker than that of Bamet-UD2, which was seen to exert a very strong cytostatic effect. CONCLUSION: Although the distance between the platinum atom and the bile acid moiety affects the in vitro Bamet reactivity with DNA, other factors determine the overall cytostatic activity of these compounds.