Enhancement of cytotoxicity of doxorubicin by verapamil in the hepatic artery infusion for liver tumors in rats

BACKGROUND: The calcium channel blocker has been demonstrated to be effective in the accumulation and retention of chemotherapeutic agents in tumor cells. METHODS: The effect of verapamil on cytotoxicity of doxorubicin was investigated in a hepatic artery infusion (HAI) for liver tumors of Walker 256 carcinosarcoma in rats. Doxorubicin was infused by way of a hepatic artery by a bolus injection intra-arterially (IA) (1 mg/kg) and a continuous infusion intra-arterially (CIA) (6 mg/kg/day for 6 days). RESULTS: Doxorubicin increased 90% and 66% in tumor tissue following HAI of verapamil by a bolus and continuous infusion (P < 0.05), respectively. However, no enhancement of the accumulation of doxorubicin in the tumor tissue was found in an intravenous administration of verapamil. The CIA infusion of verapamil with doxorubicin inhibited the tumor growth by 73% in comparison with doxorubicin only (P < 0.05). Verapamil administered intravenously (IV) could not induce this inhibitory effect. The CIA administration of verapamil reduced the serum concentration by 45% (P < 0.001) in comparison with the CIV route. Furthermore, the administration of verapamil did not increase the accumulation of doxorubicin in the normal liver and heart tissues. No enhancement of bone marrow suppression and hepatic biochemical influence by doxorubicin was revealed by the concomitant use of verapamil. CONCLUSIONS: The continuous HAI of verapamil remarkably enhanced the cytotoxicity of HAI with doxorubicin for the treatment of hepatic tumor without aggravating the side effects induced by doxorubicin.