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In vitro and in vivo modulation of multi-drug resistance with amiodarone
W T van der Graaf1, E G de Vries, D R Uges
1Department of Medical Oncology, University Hospital, Groningen, The Netherlands.
Abstract:
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.
Insights
Amiodarone (AM) and its metabolite desethylamiodarone (DEA) enhance the effectiveness of chemotherapy drugs like adriamycin (Adr) in P-glycoprotein-positive cancer cells. This combination shows potential in treating drug-resistant tumors with manageable toxicity.
Area of Science:
- Pharmacology
- Oncology
- Molecular Biology
Background:
- Drug resistance is a major challenge in cancer chemotherapy.
- P-glycoprotein (P-gp) is a key efflux pump contributing to multidrug resistance.
- Amiodarone (AM) and its metabolite desethylamiodarone (DEA) are known to interact with drug transporters.
Purpose of the Study:
- To investigate the modulatory effect of AM and DEA on drug resistance in cancer cell lines.
- To evaluate the potential of AM and DEA as chemosensitizers in combination with chemotherapeutic agents.
Main Methods:
- In vitro studies using P-gp-positive (COLO 320) and P-gp-negative (GLC4, GLC4-Adr) human cancer cell lines.
- Cytotoxicity assays with adriamycin (Adr), vincristine, and etoposide (VP16).
- Intracellular drug accumulation and DNA damage assessment.
- In vivo study involving patients with adriamycin-resistant tumors treated with Adr and AM.
Main Results:
- AM and DEA increased the cytotoxicity of Adr, vincristine, and VP16 in P-gp-positive COLO 320 cells, but not in P-gp-negative GLC4 cells.
- AM enhanced intracellular Adr accumulation, Adr-induced DNA strand breaks, and VP16-induced topoisomerase II-DNA complexes in COLO 320 cells.
- Clinical trial showed that patient serum containing AM and DEA enhanced Adr-induced cell kill in vitro.
- The combination of Adr and AM showed manageable cardiac and bone-marrow toxicity in patients, with one partial remission observed.
Conclusions:
- Amiodarone and desethylamiodarone can overcome P-glycoprotein-mediated drug resistance in cancer cells.
- The combination of amiodarone with adriamycin demonstrates potential as a therapeutic strategy for drug-resistant cancers.
- Further clinical investigation is warranted to explore the efficacy and safety of this combination therapy.