Modulation of Drug Sensitivity by Dipyridamole in Multidrug Resistant Tumor Cells in Vitro

The concept of overcoming multidnig resistance using modulators is based on the hypothesis that there will be a synergistic interaction between the modulator and the cytotoxic agent. We examined the ability of dipyridamole (DPM) to synergistically enhance drug sensitivity in drug-sensitive KB-3-1 cells and their drug-resistant variants, KB-GRCl and KBVI cells, using median effect analysis to produce a quantitative measure of the extent of synergy. The drug-resistant variants were resistant to vinblastine (VBL), colchicine (COL), and etoposide (VP-16) in the order VBL >COL >VP-16 on the basis of 50% inhibitory concentration values obtained by clonogenic assay with continuous drug exposure. The extent of staining with the monoclonal antibody HYB-241, directed at a M., 180,000 form of the mdrl gene product, correlated with drug resistance for all three drugs (r >0.92). DPM and verapamil elevated the steady state content (C�) of VBL, but there was no correlation between elevation of C� and the extent of synergy observed. DPM enhanced the cytotoxicity of VBL and COL in a synergistic manner in KB-GRCl cells, and in KBVI cells DPM interacted synergistically with VBL. VPL was synergistic with VBL only in KB-GRCl cells. No synergy was observed in the parental KB-3-1 line. These data indicate that, although both DPM and verapamil can increase C� in cells not expressing P-glycoprotein, such an increase was not associated with synergy. In cells expressing mi/r/, synergy was observed, and it was greatest for the cytotoxic agent for which expression of mdrl produced the greatest fold-resistance and enhancement of C�. However, neither the level of resistance, the level of expression of mdrl nor the ability of the modulator to alter C� accurately predicted whether the interaction would be truly synergistic. We conclude that additional factors determine the nature of the drug interaction.