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Pharmacological characterization of N-substituted phenoxazines directed toward reversing Vinca alkaloid resistance in multidrug-resistant cancer cells

JK Horton, KN Thimmaiah, FC Harwood, JF Kuttesch and PJ Houghton

Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.

Previously we reported the synthesis and partial characterization of 21 N10-substituted phenoxazines in reversing Vinca alkaloid resistance. Here we report on a subset of these compounds; we have compared their activities in increasing Vinca alkaloid accumulation and reversing drug resistance in KB-ChR8-5 and GC3/c1 (human colon carcinoma) cell lines. Results demonstrated that 1) N-substituted phenoxazines increase accumulation of vinblastine; 2) within this series, there is little correlation or ranking of activity between the two cell lines when Vinca alkaloid accumulation is compared at equal concentrations of modulator; 3) N-substituted phenoxazines demonstrate both quantitative and qualitative differences, compared with verapamil, a standard modulator; and 4) the series includes at least two compounds, 10-[3'-[N- bis(hydroxyethyl)amino]propyl]phenoxazine and 10-(N- piperidinoacetyl)phenoxazine, which increase Vinca alkaloid accumulation but do not significantly inhibit efflux. Additionally, certain of these multidrug resistance modulators significantly enhance accumulation (8-50-fold) of Vinca alkaloids in cell lines with very low or undetectable P-glycoprotein levels, where verapamil has little activity. It is concluded that at least part of the activity of some of these N-substituted phenoxazine modulators may be mediated through a P- glycoprotein-independent mechanism.

Volume 44, Issue 3, pp. 552-559, 09/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1993 by the American Society for Pharmacology and Experimental Therapeutics