Mitoxantrone Given by 120 h CVI 739 20. 21. 22. 23. 24. studies of 96 h infusion of doxorubicin in advanced breast cancer patients. EurJ Cancer Clin Oncol1989,25,505-511. Legha SS, Benjamin RS, MacKay B, et al. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 1982,96,133-139. Powis G. Anticancer drug pharmacodynamics. Cancer Chemother Pharmacoll986,14,177-183. Moore MJ, Erlichman C. Therapeutic drug monitoring in oncology. Problems and potential in antineoplastic therapy. Clin Pharmacokin 1987,13,205-227. Ackland SP, Ratain MJ, Vogelzang NJ, etal. Pharmacokinetics and pharmacodynamics of long-term continuous infusion doxorubicin. Clin Pharmacol Ther 1989,45,340-347. Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol1989,7,1748-1756. 25. Bennett CL, Sinkule JA, Schilsky RL, Senekjian E, Choi KE. Phase I clinical and pharmacologic study of 72-hour continuous infusion of etoposide in patients with advanced cancer. Cancer Res 1987,47,617-623. 26. Santini J, Milan0 G, Thyss A, et al. 5-FU therapeutic monitoring with dose adjustment leads to an imkproved therapuetic index in head and neck cancer. BrJ Cancer 1989,59,287-290. Acknowledgements-The help and the cooperation of the nursing staff of the “Unit6 de Pharmacologic Clinique” is greatly appreciated. This work was supported by a grant from Lederle Laboratories, France. EurJ Cancer, b’ol 27, No. 6, pp i.l9-744, 1991. 0277-5379:91$3.00 + 0.00 Pnnred m Greof Rnturn c 1991 Pergamon Press pit 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 and Herbert M. Pinedo 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 (rmoY1, able to reverse anthracycline resistance in vitro. Pharmacokinetic studies demonstrated a median bepridil plasma concentration of 5.3 pmol/l (range 2.6-19.3 pmol/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. EurJ Cancer, Vol. 27, No. 6, pp. 739-744,199l INTRODUCTION awaits confirmation. Anthracyclines are among the most effec- THE OCCURRENCE of drug resistance is considered as a major tive antineoplastic drugs in current use. In vitro studies have cause of chemotherapy failure in solid tumours. Several mechan- revealed that anthracyclines display crossresistance to a group isms of drug resistance have been discovered in in vitro systems of structurally and functionally unrelated cytotoxic agents. This and in animal models, but their significance in human cancer phenomenon, called multidrug resistance (MDR), is related to a decreased intracellular drug accumulation and changes in Correspondence to H.M. Pinedo, Department of Medical Oncology, intracellular distribution of drugs [l-3]. The overexpression of Free University Hospital, De Boelelaan 1117, 1087 HV Amsterdam, a 170-180 kD P-glycoprotein [4], is thought to be responsible The Netherlands. for an energy dependent outward transport of xenobiotics and The authors are at the Department ofMedical Oncology, Free University cytotoxic drugs derived from them [5, 61. It has been shown Hospital, Amsterdam; H.M. Pinedo is also at the Netherlands Cancer Institute, Amsterdam, The Netherlands. that P-glycoprotein mediated resistance to anthracyclines can Revised 4 Mar. 1991; accepted 12 Mar. 1991. be reversed in vitro by several substances, including a number of calcium channel blockers [7]. The results of clinical studies in