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

Abstract

Summary 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-' 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 6248ngml-' and 1012ngml-' 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.

Targeted drugs in metastatic colorectal cancer with special emphasis on guidelines for the use of bevacizumab and cetuximab: An Acta Oncologica expert report

“…by interaction with drug transport across the cell membrane, was considered highly promising approximately a decade ago and early clinical trials were performed also in CRC [43,44]. After failure of the approach in the most promising tumour types [11], this field seems less fruitful for further development.…”

APO866 Increases Antitumor Activity of Cyclosporin-A by Inducing Mitochondrial and Endoplasmic Reticulum Stress in Leukemia Cells

“…S2), suggesting that the potentiation effect observed with CsA may reflect an alternative mode of action of the latter. In addition to inhibiting calcineurin, CsA is also a well-known Pgp inhibitor (41)(42)(43). Thus, we reasoned that Pgp inhibition may be the mechanism underlying CsA-mediated enhancement of APO866 antileukemic activity and tested other, unrelated Pgp inhibitors in combination with APO866 to see whether they would recreate the effects of CsA.…”

Reversal of ABC Drug Transporter-Mediated Multidrug Resistance in Cancer Cells: Evaluation of Current Strategies

“…It was thereafter used as a benchmark for ABCB1 inhibitors for in vitro studies due to its high potency and low intrinsic toxicity [55,56]. Unfortunately, similarly to verapamil in clinical trials, CsA failed to achieve clinical inhibition of ABCB1 at the concentrations tested [57][58][59]. More recently, CsA was also shown to block ABCG2-mediated efflux and restore drug sensitivity in ABCG2 overexpressing cells [60,61].…”