Restoration of Drug Sensitivity by Nitroxazepine Hydrochloride in P388 Murine Leukemia Cells Resistant to Adriamycin

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Abstract
Attempts were made to reverse the acquired resistance of P388 murine leukemia utilizing non-toxic concentration of nitroxazepine hydrochloride, an antidepressant. The effect of nitroxazepine hydrochloride on the intracelluar accumulation of adriamycin and the inhibition of DNA synthesis were studied in these cells. The survival of mice bearing adriamycin-resistant P388 murine leukemia cells treated in vitro with nitroxazepine hydrochloride, adriamycin and a combination of the two drugs was also investigated. The results show that treatment of these cells with nitroxazepine hydrochloride significantly enhanced (1) the intracellular accumulation of adriamycin, (2) inhibition of DNA biosynthesis, and (3) the survival of mice transplanted with adriamycin-resistant P388 murine leukemia cells treated in vitro with a combination of nitroxazepine hydrochloride and adriamycin. The mechanism of restoration of drug sensitivity by nitroxazepine hydrochloride in adriamycin-resistant P388 cells could be due to an enhanced intracellular accumulation of adriamycin. The implications of the present investigations are promising, leaving hope for the utility of nitroxazepine hydrochloride in restoring drug sensitivity in adriamycin-resistant tumors.