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In vitro and in vivo modulation of multi‐drug resistance with amiodarone
Author(s) -
Van Der Graaf W. T. A.,
De Vries E. G. E.,
Uges D. R. A.,
Nanninga A. G.,
Meijer C.,
Vellenga E.,
Mulder P. O. M.,
Mulder N. H.
Publication year - 1991
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910480422
Subject(s) - etoposide , pharmacology , in vivo , cell culture , p glycoprotein , cytotoxicity , topoisomerase , doxorubicin , verapamil , efflux , paclitaxel , metabolite , in vitro , biology , chemistry , medicine , drug resistance , multiple drug resistance , chemotherapy , biochemistry , calcium , genetics , microbiology and biotechnology
The modulating effect on drug resistance of amlodarone (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 (Adr)‐resistant subline GLC4‐Adr (both P‐glycoprotein‐negative). AM, DEA and verapamil induced an increase in cytotoxicity of Adr, vincristine and etoposide (VP16) 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 VP16‐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 μ.M 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 toxiclty 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.