Akemi Baba

Intra-hepatic arterial administration with miriplatin suspended in an oily lymphographic agent inhibits the growth of tumors implanted in rat livers by inducing platinum-DNA adducts to form and massive apoptosis

BackgroundMiriplatin (formerly SM-11355), a novel lipophilic platinum complex developed to treat hepatocellular carcinoma, is administered into the hepatic artery using an oily lymphographic agent (Lipiodol Ultra-Fluide®) as a carrier. We clarified the usefulness of miriplatin as an agent for transarterial chemoembolization.MethodsPlatinum compounds released from miriplatin into serum, medium and Earle’s balanced salt solution were examined. Then, miriplatin and cisplatin were administered to rats bearing hepatoma AH109A tumors in livers. Platinum concentrations in tissues and DNA were assessed.ResultsMiriplatin showed a more sustained release than cisplatin. Dichloro[(1R, 2R)-1, 2-cyclohexane diamine-N, N′]platinum, the most abundant platinum compound released from miriplatin, was as effective as cisplatin in inhibiting the growth of cells. Miriplatin was selectively disposed of in tumors, maintained in tumors longer than cisplatin and caused apparent tumor regression inducing platinum-DNA adducts to form and massive apoptosis.ConclusionMiriplatin appears to be a suitable chemotherapeutic agent for transarterial chemoembolization.

Intra‐hepatic arterial administration with miriplatin suspended in an oily lymphographic agent inhibits the growth of human hepatoma cells orthotopically implanted in nude rats

Miriplatin is a lipophilic platinum complex which contains myristates as leaving groups and diaminocyclohexane as a carrier ligand. In order to examine in vivo the antitumor activities of miriplatin suspended in an oily lymphographic agent (Lipiodol Ultra‐Fluide®, LPD) against human hepatocellular carcinoma (HCC) after the intra‐hepatic arterial administration, we have developed a novel orthotopic model of HCC in which the human hepatoma cell line Li‐7 was successively implanted and maintained in the liver of nude rats. Li‐7 tumors established in nude rat livers displayed a trabecular structure similar to their original morphology, and were exclusively supplied by the hepatic artery, suggesting that they exhibited in part the conditions of human HCC. Miriplatin suspended in LPD (miriplatin/LPD) administered into the hepatic artery of this model dose‐dependently inhibited the growth of Li‐7 tumors without markedly enhancing body weight loss and caused a significant reduction in the growth rate at a dose of 400 µg/head compared to LPD alone. In addition, at the therapeutic dose, miriplatin/LPD as well as cisplatin suspended in LPD (400 µg/head) was shown to be more active than zinostatin stimalamer suspended in LPD (20 µg/head) against Li‐7 tumors after a single intra‐hepatic arterial administration. These results suggest miriplatin to be a suitable candidate for use in transarterial chemoembolization (Cancer Sci 2009; 100: 189–194)