CHARACTERIZATION OF A NOVEL BISACRIDONE AND COMPARISON WITH PSC-833 AS A POTENT AND POORLY REVERSIBLE MODULATOR OF P-GLYCOPROTEIN

Novel compounds, composed of two acridone moieties connected by a prop yl or butyl spacer, were synthesized and tested as potential modulator s of P-glycoprotein (P-gp)-mediated multidrug resistance. The propyl d erivative 1,3-bis(9-oxoacridin-10-yl)-propane (PBA) was extremely pote nt and, at a concentration of 1 mu M, increased steady state accumulat ion of vinblastine (VLB) approximate to 9-fold in the multidrug-resist ant cell line KB8-5. In contrast to the readily reversible effects of VRP and cyclosporin A on VLB uptake and similar to the effects of the cyclosporin analog PSC 833, this modulation by PBA was not fully rever sed 6-8 hr after transfer of cells to PBA-free medium. Continuous expo sure to 3 mu M PBA was nontoxic and could completely reverse VLB resis tance in KB8-5 cells. Consistent with its effects on VLB transport, th e drug resistance-modulating effect of PSC 833 was significantly more persistent than that of VRP. However, the effect of PEA was, like that of VRP, rapidly reversed once the modulator was removed from the extr acellular environment. PEA was able to compete with radiolabeled azido pine for binding to P-gp and to stimulate P-gp ATPase activity, Howeve r, both the steady state accumulation of PEA and the rate of efflux of PBA were similar in drug-sensitive KB3-1 and drug-resistant KB8-5 cel ls, suggesting that this compound is not efficiently transported by P- gp. These results indicate that PEA represents a new class of potent a nd poorly reversible synthetic modulators of P-gp-mediated VLB transpo rt.