Effects of calcium antagonists on anti-cancer drug toxicity to haematopoietic progenitor cells in normal human bone marrow.

Calcium (Ca) antagonists are promising candidates to enhance the drug sensitivity of resistant tumor cells. However, it is not yet clear whether these agents increase anti-cancer drug toxicity to normal human haematopoietic progenitor cells. In this paper, we examined the ability of Ca antagonists including verapamil, diltiazem, nicardipine, and clomipramine, to augment the toxicity of vincristine (VCR) and adriamycin (ADM) to normal bone marrow granulocyte-macrophage progenitor cells (CFU-GM) in vitro. When CFU-GM colonies were cultured for 10 days with VCR(10(-9) M) or ADM(10(-8) M) alone, the number of colonies was reduced to 73.7% +/- 13.0% (mean +/- S.D., n = 9) and 63.4% +/- 10.2% (n = 9) of those of the controls, respectively. The addition of Ca antagonists at the clinically achievable concentrations of 0.2 and 2 microM further enhanced the toxicity of these drugs; verapamil even at a lower concentration reduced the colony number to 36.8% +/- 8.9% (n = 4) for VCR and 32.8% +/- 9.5% (n = 4) for ADM. Nicardipine also reduced CFU-GM to a lesser degree in co-culture with ADM. Ca antagonists alone did not suppress CFU-GM. No enhancement of toxicity was mediated by Ca antagonists at lower VCR or ADM concentrations (10(-10) M or less). In addition, after a short-term (24 h) co-incubation of VCR or ADM with Ca antagonists, no significant enhancement of toxicity was observed. These results indicated that the combination of VCR or ADM with Ca antagonists may enhance toxicity to normal human CFU-GM under certain circumstances.