SUPPRESSION OF P-GLYCOPROTEIN EXPRESSION AND MULTIDRUG-RESISTANCE BY DNA CROSS-LINKING AGENTS

Overexpression of the trans-membrane drug efflux pump P-glycoprotein i s one of the major mechanisms by which cancer cells develop multidrug resistance, We demonstrated previously that noncytotoxic doses of vari ous genotoxic chemicals, particularly DNA cross-linking agents, prefer entially altered expression of inducible genes. These effects occurred principally at the transcriptional level and were closely correlated temporally with DNA damage, Because the mdr1 gene coding for P-glycopr otein has been reported to be highly inducible, we were interested in the effects of genotoxic cancer chemotherapy agents on its expression, We report that the DNA cross-linking agent mitomycin C significantly suppressed mRNA and protein expression of P-glycoprotein and decreased the rate of drug efflux. Mitomycin C pretreatment also significantly increased the sensitivity of cancer cells to subsequent killing by the P-glycoprotein substrate doxorubicin, decreasing the ED50 by 5- to 10 -fold, Suppression of P-glycoprotein expression was also observed with subtoxic doses of the DNA cross-linking agents cisplatin, BMS181174, and chromium(IV). These effects occurred in both human and rodent cell lines; in cell lines derived from colon, breast, leukemia, neuroblast oma, and hepatoma tumors; and under both monolayer and ''spheroid'' cu lture conditions, These results suggest the basis for novel clinical c ancer chemotherapy regimens aimed at drug-resistant tumors, in which a subchemotherapeutic dose of a DNA cross-linking agent is used to modu late the multidrug resistance phenotype prior to treatment with a seco nd cytotoxic agent.