In vitro and in vivo modulation of multi-drug resistance with amiodarone.
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 (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 microM 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.
van der Graaf
W T
WT
Department of Medical Oncology, University Hospital, Groningen, The Netherlands.
de Vries
E G
EG
Uges
D R
DR
Nanninga
A G
AG
Meijer
C
C
Vellenga
E
E
Mulder
P O
PO
Mulder
N H
NH
D000328:Adult; D000638:Amiodarone / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001692:Biological Transport / Q000187:drug effects; D018288:Carcinoma, Small Cell; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms; D004249:DNA Damage; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D005047:Etoposide / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D014410:Tumor Stem Cell Assay; D014750:Vincristine / Q000494:pharmacology*
D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D000638:Amiodarone