Abstract
Several members of a group of compounds developed to treat stroke and trauma of the central nervous system are shown also to reverse multidrug resistance in human KB-V1 cells. The most potent reversal agents studied are 21-aminosteroid derivatives (lazaroids), tirilazad mesylate (tirilazad, U-74006F) and U-74389F. Tirilazad sensitizes resistant human cells (KB-V1) to killing by vinblastine by 66-fold, but does not change the sensitivity of the nonresistant parental line, KB-3-1, to vinblastine. KB-V1 cell membranes have high levels of P-glycoprotein, a protein that acts as an efflux pump and is thought to be the major cause of multidrug resistance in these cells. Tirilazad inhibits the photoaffinity labeling of P-glycoprotein with [3H]azidopine in KB-V1 cells more effectively than does verapamil, a standard reversal agent. In addition, tirilazad causes, the increased accumulation of [3H] vinblastine in multidrug resistant KB-V1 cells. Studies of the resistance reversal potential of related compounds suggest that the complex amine portion of tirilazad is important for its reversal activity, while the steroid portion is less important.
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Abraham, I., Wolf, C.L. & Sampson, K.E. Non-glucocorticoid steroid analogues (21-aminosteroids) sensitize multidrug resistant cells to vinblastine. Cancer Chemother. Pharmacol. 32, 116–122 (1993). https://doi.org/10.1007/BF00685613
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DOI: https://doi.org/10.1007/BF00685613