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

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 intracellular 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.

Modulation of Sensitivity to Mitoxantrone in Human Chronic Myeloid Leukemia Cells by the Antidepressant Sintamil

“…Re cent evidence indicates that these agents inactivate the membrane glycoproteins which mediate enhanced ef flux of many structurally and functionally similar/ dissimilar drugs [19,20]. We have observed that SNT can enhance the accumulation and cytotoxicity of Adriamycin in Adriamycin-resistant cell lines [14].…”

“…This is based on the evidence that SNT and its structural analogue, the anticalmodulin agent chlorimipramine. could enhance the Adriamy cin cytotoxicity [13,14] in drug-resistant tumor cells. Our studies demonstrate that SNT can bring about enhanced and irreversible DNA biosynthesis inhibi tion by MTN from the relatively nontoxic concentra tions in CML cells and is suggestive of therapeutic utility in the clinics.…”

Effect of Alterations in Permeability by Nonionic Surfactants on Adriamycin Cytotoxicity in Murine Tumor Models in vitro

“…22]. Various compounds which are clinically utilised in ailments other than cancer, such as verapamil [7,10,23], trifluoperazine [11], nitroxazepine [24] and chloimipramine [25] have been shown to potentiate the activity of Adr in both drug-sensitive and drug-resistant cells. Tween 80 has also been shown to enhance the efficacy of various antitumor agents in vitro and in vivo, in experimental tumor models [14,15], Kerr et al [16] have recently reported that B-30 enhances the cellular uptake of Adr and improves the cytotoxicity of Adr in monolayer, clonogenic and spheroid culture systems.…”