NOVEL TETRAMETHYLPIPERIDINE-SUBSTITUTED PHENAZINES ARE POTENT INHIBITORS OF P-GLYCOPROTEIN ACTIVITY IN A MULTIDRUG-RESISTANT CANCER CELL-LINE

The multidrug resistance (MDR)-neutralizing and cytotoxic properties o f 16 novel tetramethylpiperidine (TMP)-substituted phenazines were com pared with those of clofazimine and B669 using a P-glycoprotein (P-gp) -expressing undifferentiated, human leukemia cell line (K562/MMB). Unc hlorinated TMP-substituted phenazine molecules were more cytotoxic tha n their chlorinated counterparts, while the halogenated molecules, esp ecially those with chlorine atoms at position 3 on the aniline and phe nyl rings, were less cytotoxic bur more effective as chemosensitizing, P-gp-neutralizing agents. One of the TMP-substituted phenazines, B412 1, increased the sensitivity of K562/MMB cells to vinblastine by 100-f old. TMP-substituted phenazines are a novel class of pharmacologic ant i-cancer agents with both direct cytotoxic, as well as MDR-neutralizin g anti-tumor properties.