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In vivo reversibility of multidrug resistance by the MDR-modulator dexniguldipine (niguldipine derivative B859-35) and by verapamil.

The newly synthesized dihydropyridine derivative B859-35 was previously shown in vitro to be highly effective in reversing multidrug resistance (MDR) of P-glycoprotein positive tumor cell lines, such as the adriamycin (ADR) resistant erythroleukemia F4-6RADR cells. In the current study B859-35 was investigated for its efficiency in reversing MDR in an in vivo tumor model for preclinical testing of MDR-modulators. F4-6RADR cells were injected into the right flank of nude mice while the parent cells were injected into the left flank. The animals were treated i.p. with ADR (9.0 mg/kg body weight) combined with B859-35 (5, 10, or 25 mg/kg) or, for comparison and validation, with verapamil (VRP) (75 mg/kg). The effects of ADR and the MDR-modulator combination were evaluated by histological morphometry of the tumors. While ADR alone was shown to be ineffective in resistant cells, the combinations of ADR + B859-35 as well as of ADR + VRP were highly active in reducing the number of viable cells in the resistant tumor nodule by 67 +/- 9% or by 53 +/- 11% of controls. This model provides evidence that even in vivo, MDR modulators can be effective in reversing drug resistance. In addition, it presents a potentially useful and rapid preclinical system for in vivo studies on the modification of drug resistance.