flunarizine and Melanoma

Flunarizine, a calcium antagonist commonly employed in therapy for vascular diseases, enhances the in vitro and in vivo antitumor activity of vincristine on B16 melanoma cells. In the presence of flunarizine higher intracellular levels of vincristine were observed in vitro and for a longer time. B16 melanoma bearing mice treated with both the drugs presented a median survival time that was significantly longer than that of the controls. The possible mechanism of the enhancement is herein discussed.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Division; Cell Line; Drug Resistance; Drug Synergism; Flunarizine; Melanoma; Mice; Mice, Inbred C57BL; Vincristine

Verapamil had previously been shown to increase cellular melphalan uptake and cytotoxicity in fibrosarcomas, and increased the area under the blood concentration versus time curve (AUC) for melphalan in CBA mice. Verapamil (10 mg kg-1 i.p.) had no effect on the fractional distribution of cardiac output (FDCO), measured with 86Rb-rubidium chloride, to subcutaneous fibrosarcomas. 14C-Melphalan uptake by FS13 fibrosarcomas was increased 60 min after verapamil (10 mg kg-1 i.p.), but not after lower doses which did not affect the AUC. Flunarizine (5 mg kg-1 i.p.) also had no effect on FDCO to FS13 fibrosarcomas, and tended to increase 14C-melphalan content of blood and the fibrosarcomas and to promote growth delay by melphalan. Alcohol increased FDCO to FS13 fibrosarcomas, maximally at a 1:20 dilution in saline, but had no effect on 14C-melphalan uptake or growth delay. Thus, melphalan cytotoxicity correlated with tumour melphalan uptake, and both followed changes in the AUC for melphalan but not changes in FDCO. In these murine fibrosarcomas melphalan uptake and cytotoxicity were not limited by blood flow. In subcutaneous human melanoma HX46 xenografts, verapamil had no effect on the FDCO, nor on 14C-melphalan uptake, and did not affect blood 14C-melphalan levels, suggesting absence of effects on the AUC and on cellular uptake. Alcohol did not increase the FDCO to HX46 xenografts, providing evidence for a different vascular supply.

Topics: Animals; Cinnarizine; Drug Synergism; Ethanol; Female; Fibrosarcoma; Flunarizine; Humans; Male; Melanoma; Melphalan; Mice; Mice, Inbred CBA; Regional Blood Flow; Verapamil