Abstract
The concept of overcoming multidrug 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-GRC1 and KBV1 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 Mr 180,000 form of the mdr1 gene product, correlated with drug resistance for all three drugs (r ≥ 0.92). DPM and verapamil elevated the steady state content (Css) of VBL, but there was no correlation between elevation of Css and the extent of synergy observed. DPM enhanced the cytotoxicity of VBL and COL in a synergistic manner in KB-GRC1 cells, and in KBV1 cells DPM interacted synergistically with VBL. VPL was synergistic with VBL only in KB-GRC1 cells. No synergy was observed in the parental KB-3-1 line. These data indicate that, although both DPM and verapamil can increase Css in cells not expressing P-glycoprotein, such an increase was not associated with synergy. In cells expressing mdr1, synergy was observed, and it was greatest for the cytotoxic agent for which expression of mdr1 produced the greatest fold-resistance and enhancement of Css. However, neither the level of resistance, the level of expression of mdr1, nor the ability of the modulator to alter Css accurately predicted whether the interaction would be truly synergistic. We conclude that additional factors determine the nature of the drug interaction.
