The natural resistance of human chronic myeloid leukemia cells to adriamycin (ADR) was overcome by using the cell membrane modulator verapamil (VRP). The studies were done in vitro. [³H] thymidine incorporation inhibition was used as a measure of cytotoxicity. The results clearly show an increase in the effectiveness of ADR when used along with VRP, which may be due to the changes in the cell membrane brought about by VRP.

The biochemical modulation of tumor cell response to increase the cytotoxicity of Hydroxyurea (HU), directed at the ribonucleotide reductase enzyme, has been studied in in vitro. Mice bearing ascites tumor models such as L1210 leukemia, Sarcoma 180 (S180) and Ehrlich ascites tumor (EAT) were employed in this study. The cytotoxicity of HU alone at various concentrations was dose dependent and showed the following order of sensitivity; L1210 greater than EAT greater than S180. The hydrophobic iron-chelating agent 2,2-bipyridyl significantly potentiated the antitumor activity of HU in all the murine tumor models studied. In contrast, hydrophilic iron-chelator, Desferal, did not show any cytotoxicity when combined with HU. The present study demonstrated the factors influencing the amelioration of HU cytotoxicity and possible therapeutic use of iron-chelating agents alone and with HU for better therapeutic results in clinics.

The utility of mitoxantrone (MTN) in the cytotoxic chemotherapy of human chronic myeloid leukemia (CML) is envisaged. In the present study we employed marginally toxic concentration of MTN and the antidepressant sintamil (SNT) as drug response modulator to evaluate the heterogenous response to chemotherapy by CML cells and to potentiate the cytotoxicity of MTN. In vitro results from 26 different CML blood samples displayed variation in cytotoxicity of MTN (1 μg/ml) alone and in the resulting synergistic inhibition of DNA biosynthesis with the combination of SNT (10 μg/ml). Of the 26 samples studied, 14 samples indicated synergistic, 2 additive, and 11 less than additive cytotoxic effects due to the combined treatment with MTN and SNT. The cytotoxicity induced by MTN alone and the combination with SNT was found to be irreversible. Data suggest the utility of MTN alone and in combination with SNT in the treatment of CML and warrant further studies for the evaluation in the clinics.

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.

Calcium channel-blocking agent verapamil has been established to be an effective drug to modulate the action of many anticancer drugs. In this study, we examined the effect of verapamil on the cytotoxicity of mitoxantrone in human chronic myeloid leukemia (CML) cells. Mitoxantrone alone exhibited dose-dependent inhibition of DNA biosynthesis in CML cells. The addition of verapamil (3.3 μM) enhanced the responsiveness of CML cells to mitoxantrone (1 μg/ml) cytotoxicity indicated by significant increased inhibition of thymidine incorporation (p <0.001). The present study demonstrates the possible efficacy of verapamil in the chemotherapy of CML with mitoxantrone.