Resveratrol protects against arsenic trioxide-induced cardiotoxicity in vitro and in vivo.

BACKGROUND AND PURPOSE: The clinical use of arsenic trioxide (As(2)O(3)), a potent antineoplastic agent, is limited by its severe cardiotoxic effects. QT interval prolongation and apoptosis have been implicated in the cardiotoxicity of As(2)O(3). The present study was designed to evaluate the effects of resveratrol on As(2)O(3)-induced apoptosis and cardiac injury. EXPERIMENTAL APPROACH: In a mouse model of As(2)O(3)-induced cardiomyopathy in vivo, QT intervals and plasma enzyme activities were measured; cardiac tissues were examined histologically and apoptosis assessed. In H9c2 cardiomyocyte cells, viability, apoptosis, generation of reactive oxygen species (ROS) and cellular calcium levels were measured. KEY RESULTS: In the mouse model, resveratrol reduced As(2)O(3)-induced QT interval prolongation and cardiomyocyte injury (apoptosis, myofibrillar loss and vacuolization). In addition, increased lactate dehydrogenase activity and decreased activities of glutathione peroxidase, catalase and superoxide dismutase were observed in the plasma of As(2)O(3)-treated mice; these changes were prevented by pretreatment with resveratrol. In As(2)O(3)-treated H9c2 cardiomyocytes, resveratrol significantly increased cardiomyocyte viability and attenuated cell apoptosis as measured by acridine orange/ethidium bromide staining, TdT-mediated dUTP nick end labelling assay and caspase-3 activity. As(2)O(3)-induced generation of ROS and intracellular calcium mobilization in H9c2 cells was also suppressed by pretreatment with resveratrol. CONCLUSIONS AND IMPLICATIONS: Our results showed that resveratrol significantly attenuated As(2)O(3)-induced QT prolongation, structural abnormalities and oxidative damage in the heart. In H9c2 cardiomyocytes, resveratrol also decreased apoptosis, production of ROS and intracellular calcium mobilization induced by treatment with As(2)O(3). These observations suggested that resveratrol has the potential to protect against cardiotoxicity in As(2)O(3)-exposed patients.

Preliminary result of mixed bacterial vaccine as adjuvant treatment of hepatocellular carcinoma.

Mixed bacterial vaccine (MBV) was employed in the multi-modality treatment of hepatocellular carcinoma (HCC) during 1985-1988. Thirty eight patients undergoing palliative resection and cisplatin therapy (Series 1) and 48 patients with unresectable HCC who received hepatic artery ligation + intraarterial cisplatin infusion + radiotherapy (Series 2) were randomized to receive MBV or not. In series 1, the 1- and 2-year survival rates of MBV group and control were 75% vs 58% (P = 0.19) and 45% vs 39% (P = 0.23). In series 2, the 1-, 2- and 3-year survival rates were 59%, 41% and 41% for MBV group and 39%, 25% and 20% for the control, respectively (P1 = 0.07, P2 = 0.09, P3 = 0.07). In addition, MBV improved the "second look" resection rate to 40% as compared to 17% in the control (P greater than 0.05). MBV could also prevent such immunosuppression as decrease of macrophage activity caused by radiotherapy. We consider MBV a potential nonspecific immunostimulant in the multimodality treatment of HCC.