A phase II study of epidoxorubicin in colorectal cancer and the use of cyclosporin-A in an attempt to reverse multidrug resistance

• Published in: British journal of cancer 1991-08, Vol.64 (2), p.361-364
• Main Authors: Verweij, J, Herweijer, H, Oosterom, R, van der Burg, M E, Planting, A S, Seynaeve, C, Stoter, G, Nooter, K
• Format: Article
• Language: English
• Subjects: Adult; Aged; Colorectal Neoplasms - drug therapy; Cyclosporins - administration & dosage; Cyclosporins - blood; Cyclosporins - pharmacology; Drug Resistance; Epirubicin - adverse effects; Epirubicin - metabolism; Epirubicin - therapeutic use; Female; Flow Cytometry; Humans; In Vitro Techniques; Leukopenia - chemically induced; Male; Middle Aged
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.1991.307

We determined the ability of the multidrug resistance (MDR) reversal agent cyclosporin-A to increase anthracycline drug accumulation in colorectal tumour cells in vitro, using the technique of on-line flow cytometry. Data of four previously untreated patients showed that cyclosporin-A can increase intracellular net-uptake of daunorubicin. A phase II study was initiated in 24 colorectal cancer patients. They received cyclosporin-A at a dose of 3 mg kg-1 over 1 h as i.v. infusion, at 7 h and at 1 h preceding cytotoxic drug administration. At the end of the second cyclosporin-A administration epidoxorubicin 90 mg m-2 was administered as i.v. bolus. Cycles were repeated every 3 weeks. Median cyclosporin-A peak blood levels and levels at 18 h after cytotoxic drug administration appeared to be 6248 ng ml-1 and 1012 ng ml-1 respectively. Only one partial response was observed, despite these high cyclosporin-A levels. Cyclosporin-A did not cause major toxicity, only a 29% incidence of hot flushes was observed. Epidoxorubicin toxicities were as expected but the frequency of severe leucocytopenia was striking. This treatment schedule can not be considered active in colorectal cancer.