DIPYRIDAMOLE INCREASES VP16 GROWTH-INHIBITION, ACCUMULATION AND RETENTION IN PARENTAL AND MULTIDRUG-RESISTANT CHO CELLS

Dipyridamole (DP) has been shown to reverse multidrug resistance (MDR) via interactions with P-glycoprotein (P-gp). The effect of DP on VP16 growth inhibition was investigated in parental (CHO-K1) and MDR (CHO- Adr(r)) Chinese hamster ovary cells. CHO-Adr(r) cells were 18-fold res istant to VP16 and intracellular accumulation was 28% less than in CHO -KI cells. DP reduced the resistance of CHO-Adr(r) to VP16 by a factor of 2-3 and caused a similar potentiation of VP16 growth inhibition in the parental cells. A time-dependent increase in intracellular VP16 a ccumulation, which was similar in both cell lines, was caused by DP. T he intracellular retention of VP16 was increased 2- to 3-fold by DP in both cell lines. The magnitude of the effect of DP on all three param eters measured was similar (2- to 4-fold), suggesting that the increas ed growth inhibition was related to increased intracellular exposure t o VP16 owing to the inhibition of the efflux of VP16 by DP. However, s ince the effect of DP was similar in both parental and P-gp-overexpres sing cells it is unlikely that the potentiation of VP16 by DP is media ted via an interaction with P-gp.