Diltiazem potentiation of doxorubicin cytotoxicity and cellular uptake in Ehrlich ascites carcinoma cells.

Abstract

The calcium channel blocker diltiazem, which possesses coronary vasodilator activity, greatly enhanced the cytotoxicity of doxorubicin in Ehrlich ascites carcinoma cells. 20% of the doxorubicin-treated tumor-bearing animals (2 mg/kg, every other day, three doses) survived, with a mean survival time of 35 days. However, pretreatment with diltiazem increased survival to 70% with a mean survival time of 43 days. Diltiazem treatment increased the intracellular level of doxorubicin, and there was a good correlation between the high cellular level of doxorubicin and its cytotoxic activity. In tumor-bearing animals pretreated with diltiazem, doxorubicin showed a pronounced inhibitory effect on cellular DNA, RNA content and acid phosphatase activity of tumor cells. In addition, there was a marked increase in cellular cholesterol and lipid contents. This study may suggest the benefit of using diltiazem to potentiate the cytotoxic effect of doxorubicin, allowing its dose and consequently the serious side effects to be reduced.