P-GLYCOPROTEIN SUBSTRATES AND ANTAGONISTS CLUSTER INTO 2 DISTINCT GROUPS

To gather further insight into the interaction between P-glycoprotein (Pgp) and its substrates, 167 compounds were analyzed in multidrug res istant human colon carcinoma cells. These compounds were selected from the National Cancer Institute Drug Screen repository using computer-g enerated correlations with known Pgp substrates and antagonists. The c ompounds were prospectively defined as Pgp substrates if cytotoxicity was increased greater than or equal to 4-fold by the addition of cyclo sporin A (CsA) and as Pgp antagonists if inhibition of efflux increase d rhodamine accumulation by 4-fold. Among the 84 agents that met eithe r criterion, 35 met only the criterion for substrates, 42 met only the criterion for antagonists, and only seven met both criteria. Thus, co mpounds interacting with Pgp form two distinct groups: one comprising cytotoxic compounds that are transported and have poor or no antagonis tic activity and a second comprising compounds with antagonistic activ ity and no evidence of significant transport. Vinblastine accumulation and kinetic studies performed on a subset of 18 compounds similarly d ifferentiated substrates and antagonists, but inhibition of H-3-azidop ine labeling and induction of ATPase activity did not. These data supp ort an emerging concept of Pgp in which multiple regions instead of sp ecific sites are involved in drug transport.