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

Coenraad K. van Kalken, Jacobus J M van der Hoeven, Jan de Jong, Giuseppe Giaccone, Gerrit Jan Schuurhuis, Paul A. Maessen, Wouter M D Blokhuis, Wim J F van der Vijgh, Herbert M. Pinedo

Research output: Contribution to journalArticle

Abstract

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 μmol/l, able to reverse anthracycline resistance in vitro. Pharmacokinetic studies demonstrated a median bepridil plasma concentration of 5.3 μmol/l (range 2.6-19.3 μmol/l, at the time of administration of the anthracycline. No acute cardiac toxicity was observed and apparently bepridil 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.

Original languageEnglish (US)
Pages (from-to)739-744
Number of pages6
JournalEuropean Journal of Cancer and Clinical Oncology
Volume27
Issue number6
DOIs
StatePublished - 1991
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    van Kalken, C. K., van der Hoeven, J. J. M., de Jong, J., Giaccone, G., Schuurhuis, G. J., Maessen, P. A., Blokhuis, W. M. D., van der Vijgh, W. J. F., & Pinedo, H. M. (1991). Bepridil in combination with anthracyclines to reverse anthracycline resistance in cancer patients. European Journal of Cancer and Clinical Oncology, 27(6), 739-744. https://doi.org/10.1016/0277-5379(91)90178-G