PMID: 8450465Mar 1, 1993Paper

In vivo reversal of doxorubicin resistance by a new tiapamil analog Ro11-2933

The Journal of Pharmacology and Experimental Therapeutics
M A Alaoui-JamaliG Batist

Abstract

The effectiveness of a calcium antagonist analog Ro11-2933 to modulate doxorubicin (DOX) response in DOX-sensitive (WT) and -resistant (DOXr, 200-fold) cell lines was investigated and compared to verapamil (VP) in vitro and in vivo in rats bearing mammary carcinoma using equivalent nontoxic doses. In vitro exposure to a nontoxic concentration of Ro11-2933 (2 microM) normalizes the DOX accumulation defect observed in DOXr cells, increases DOX-induced DNA single-strand breaks and effectively sensitizes DOXr cells to DOX. Ten microM VP was required to obtain an effect equivalent to that seen with 2 microM Ro11-2933. Intravenous administration of DOX at 5 mg/kg to the rat bearing the DOXr tumors has no significant therapeutic effect on tumor growth (P > .5), whereas it was found effective in inhibiting the growth of WT tumors (P < .05). Ro11-2933 or VP administered alone has no significant effect on tumor growth as compared to a saline-treated group (P > .1). Combination of Ro11-2933 with DOX effectively inhibits DOXr tumor growth as compared to DOX alone. Combination of DOX with VP was found less effective than Ro11-2933 and the results were not statistically significant from DOX treatment alone (P > .5). Our data demonstrate that...Continue Reading

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