Verapamil enhances antitumor activity without increasing myeloid toxicity.
The effectiveness of chemotherapy is limited by drugs' resistance and toxicity to normal host cells. Verapamil increases the cytotoxicity of the Vinca alkaloids and doxorubicin hydrochloride (Adriamycin) in tissue culture. In this experiment the effect of verapamil (VER) on the cytotoxicity of vincristine sulfate (VCR) and 5-fluorouracil (5-FU) was studied with the use of an intravenous lung colonization model. After receiving 5 X 10(4) B16 F10 cells intravenously, mice were randomized into six groups and treated with intraperitoneal injections of saline solution, VER, VCR, VCR plus VER, 5-FU, or 5-FU plus VER. In the first experiment, mice were killed on day 22 and lung colonies counted. In subsequent experiments, animals were monitored until death. The addition of VER to VCR significantly decreased pulmonary tumor formation (14 versus 47 colonies; p = 0.05). This was associated with an increase in mean survival from 40.4 to 53.7 days (p = 0.05). Although the addition of VER to 5-FU also decreased pulmonary tumor colony formation (26 versus 73 colonies; p = 0.001), there was no significant prolongation of survival with this treatment. A quantitative clonal culture of granulocyte-macrophage progenitor cells (GM-CFC) was used to assess the effect of VER on bone marrow toxicity. The addition of 5 mumol VER to 5-FU (5 X 10(-3) to 5 X 10(-7) mol/L) or VCR (5 X 10(-5) to 5 X 10(-9) mol/L) did not significantly reduce GM-CFC growth compared with treatment with either drug alone. In vivo marrow toxicity assessed 18 hours after a single drug injection was also not increased by the addition of VER to VCR or 5-FU. In this model, VER enhances the oncolytic effect of both VCR and 5-FU without a concomitant increase in toxicity to normal host marrow progenitor cells.
D000818:Animals; D000970:Antineoplastic Agents; D001853:Bone Marrow / Q000187:drug effects*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; D014750:Vincristine; D014700:Verapamil; D005472:Fluorouracil