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Amiodarone-induced Enhancement of Doxorubicin and 4'-Deoxydoxorubicin Cytotoxicity to Rat Colon Cancer Cells in Vitro and in Vivo¹

Research Group on Digestive Tumors, INSERM U.252, Faculty of Medicine, Dijon, 21033 France

The mechanisms of the resistance of intestinal cancer to anthracyclines were studied on an experimental model of rat colon cancer cells. The accumulation of anthracyclines in the nucleus of living cancer cells was observed by fluorescence microscopy. This accumulation depended on both the capacity of anthracyclines to penetrate into the cell and the activity of an efflux mechanism extruding the drug from the cell. We found that 4'-deoxydoxorubicin was superior to 4 other anthracyclines in its capacity to penetrate into confluent colon cancer cells. Amiodarone, an antiarrhythmic agent used in cardiology, inhibited the efflux mechanism efficiently and increased the toxicity of anthracyclines to the colon cancer cells. Association of amiodarone and 4'-deoxydoxorubicin was able to cure 5 of 13 rats that had been inoculated i.p. previously with syngeneic colon cancer cells. This association could be of interest in the treatment of human colon cancer.

¹ This work was supported by a grant from the Caisse Nationale d'Assurances Maladies and received help from the French League against Cancer.

² Present address: Centre G. F. LeClerc, Dijon, 21000 France.

³ To whom requests for reprints should be addressed.

Received 11/ 8/84. Revised 7/12/85. Accepted 10/21/85.

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