title: A phase II study of epidoxorubicin in colorectal cancer and the use of cyclosporin-A in an attempt to reverse multidrug resistance.
abstract: 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.
authors.affiliation: Department of Medical Oncology, Rotterdam Cancer Institute/Daniel den Hoed Kliniek, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Verweij
authors.forename: H
authors.initials: H
authors.lastname: Herweijer
authors.forename: R
authors.initials: R
authors.lastname: Oosterom
authors.forename: M E
authors.initials: ME
authors.lastname: van der Burg
authors.forename: A S
authors.initials: AS
authors.lastname: Planting
authors.forename: C
authors.initials: C
authors.lastname: Seynaeve
authors.forename: G
authors.initials: G
authors.lastname: Stoter
authors.forename: K
authors.initials: K
authors.lastname: Nooter
mesh_terms: D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D003524:Cyclosporins / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D004351:Drug Resistance; D015251:Epirubicin / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged
chemical_list: D003524:Cyclosporins; D015251:Epirubicin