Non-glucocorticoid steroid analogues (21-aminosteroids) sensitize multidrug resistant cells to vinblastine.
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.
Abraham
I
I
Upjohn Company, Kalamazoo, MI 49001.
Wolf
C L
CL
Sampson
K E
KE
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001386:Azides / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects*; D004095:Dihydropyridines / Q000378:metabolism; D004347:Drug Interactions; D004351:Drug Resistance; D006801:Humans; D007624:KB Cells; D008562:Membrane Glycoproteins / Q000378:metabolism; D011281:Pregnatrienes / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000378:metabolism / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001386:Azides; D004095:Dihydropyridines; D008562:Membrane Glycoproteins; D011281:Pregnatrienes; C074965:U 74389F; D014747:Vinblastine; C041130:azidopine; D014700:Verapamil; C053355:tirilazad