Bepridil in combination with anthracyclines to reverse anthracycline resistance in cancer patients

The use of calcium antagonists as multidrug resistance reversing agents is limited by acute cardiac toxicity which, for verapamil, becomes prohibitive when concentrations in plasma approach those required in vitro for its action. A new calcium antagonist, bepridil, is as active as verapamil in reversing drug resistance in vitro. In addition, bepridil has some more favourable pharmacological properties compared with verapamil and other calcium antagonists. 14 patients with progressive advanced cancer, resistant to doxorubicin or epirubicin, were treated with the same anthracycline in combination with bepridil. Bepridil was administered in a continuous 36 h infusion at 22 mg/kg/36 h, with a dose scheme which should result in a steady state plasma concentration of approximately 5 mumol/l, able to reverse anthracycline resistance in vitro. Pharmacokinetic studies demonstrated a median bepridil plasma concentration of 5.3 mumol/l (range 2.6-19.3 mumol/l), at the time of administration of the anthracycline. No acute cardiac toxicity was observed and apparently bepiridil did not induce an increase or change in anthracycline toxicity. However, 2 patients developed overt chronic heart failure after treatment discontinuation, which caused 1 patient's death, and a significant reduction in left ventricular ejection fraction was seen in 4 patients. This chronic cardiac toxicity could be related to the total anthracycline dose received. 5 patients attained short lasting minor responses, 3 had stable disease and 6 progressed. Immunohistochemical studies in 7 tumours failed to reveal P-glycoprotein expression. Further trials with escalating doses of bepridil in combination with multiple drug resistance related anticancer agents are warranted.