Doxorubicin, vincristine, and actinomycin-D, but not teniposide, require long-lasting uninterrupted verapamil pressure to overcome drug resistance in multidrug-resistant cells.

: The cytotoxic efficacy of doxorubicin (DOX), vincristine (VCR), actinomycin-D (ACT-D), and teniposide (VM-26) toward the LoVo and SW948 multidrug-resistant (MDR) cell sublines was significantly enhanced by the concomitant presence of verapamil (VER) during pharmacological treatment (1-h exposure) without, however, achieving a complete reversion of the MDR phenotype. Long-lasting VER in the culture medium, at the end of the combined drug+VER treatment, conferred to DOX, VCR, and ACT-D cytotoxic efficacy roughly similar to that exerted on the drug-sensitive parent cell lines. On the contrary, no enhancement of VM-26 cytotoxic efficacy was derived from continuous VER treatment. Enhancement of DOX, VCR, and ACT-D cytotoxic efficacy requires that VER be present in an uninterrupted manner in the culture medium since brief interruptions (15 to 60 min) in the VER pressure completely counteract any effect. These findings offer new insight into the modalities of pharmacological treatment that MDR cells require to obtain a complete reversion of cellular resistance to the various drug families included in the MDR spectrum.