In vitro and in vivo modulation of multi-drug resistance with amiodarone

✍ Scribed by W. T. A. Van Der Graaf; E. G. E. De Vries; D. R. A. Uges; A. G. Nanninga; C. Meijer; E. Vellenga; P. O. M. Mulder; N. H. Mulder

• Publisher: John Wiley and Sons
• Year: 1991
• Tongue: French
• Weight: 860 KB
• Volume: 48
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.2910480422

✦ Synopsis

The modulating effect on drug resistance of amiodarone (AM) and its metabolite desethylamiodarone (DEA) was studied in a P-glycoprotein-positive human colon carcinoma cell line COLO 320, and a human small-cell lung carcinoma cell line GLC4 and its adriamycin (Adrkresistant subline GLC4-Adr (both P-glycoprotein-negative). AM, DEA and verapamil induced an increase in cytotoxicity of Adr, vincristine and etoposide (VPl6) in COLO 320 cells, while in the GLC4 and GLC4-Adr cell line no effect was seen. In the COLO 320 cell line, AM caused more intracellular, and especially intranuclear, fluorescence of Adr and more Adr-induced DNA strand breaks as compared to Adr alone. Moreover, an increase in VPI 6-induced topoisomerase II-DNA complexes was observed when AM was added. Competition between AM and Adr for the same efflux pump was suggested in efflux studies. The colony-forming unit granulocyte macrophage (CFU-GM) assay showed no increase in cytotoxicity of Adr when AM was added. Fourteen patients with Adr-resistant tumors were treated with Adr and AM. In these patients, peak serum levels of AM plus DEA of 10 p-n were reached. Patient serum (20%) obtained after the first i.v. AM infusion induced in vitro significantly more cell kill of Adr in COLO 320 cells. Apart from a transient first-degree AV block in one patient, no cardiac toxicity was observed with the combination of Adr and AM. Bone-marrow toxicity was the same as expected from Adr alone in these patients. One of the 13 evaluable patients obtained a partial remission.