Tumor-specific expression of anti-mdr1 ribozyme selectively restores chemosensitivity in multidrug-resistant colon-adenocarcinoma cells

P-glycoprotein (Pgp)-conferred multidrug resistance (MDR) is expressed in c ancer and in normal colon tissues and has important physiological functions . In order to selectively reverse MDR in malignant tissue without disruptin g the function of normal colonocytes, a retroviral vector (pCEAMR) containi ng anti-mdrI ribozyme coupled to the carcinoembryonic-antigen (CEA) promote r was constructed and introduced into resistant colon-cancer cells (SW1116R ) that produce CEA and into control resistant cells (HeLaK) that do not pro duce CEA. Anti-mdrI ribozyme was expressed in SW1116R cells but not in HeLa K cells. Subsequently, the expression of mdrI mRNA and Pgp decreased signif icantly in the transfected SW1116R cells, and was even lower than in parent non-resistant SW1116 cells. The functional ability of Pgp to facilitate rh odamine 123 (Rh123) efflux showed that the transfected SW1116R cells with l ow Pgp expression retained Rh123, whereas non-transfected SW1116R cells wit h high Pgp expression released the dye quickly. There was no difference in mdr1 mRNA or in Pgp between nontransfected and transfected HeLaK cells. Dru g resistance to doxorubicin (DOX) decreased 93.1% in the transfected SW1116 R cells, while no change in drug resistance occurred in the infected HeLaK cells. DOX could clearly inhibit the growth of transfected SW1116R tumors b ut had no effect on untransfected and on transfected HeLaK cells in vivo. T hese results indicate that our anti-mdr1 ribozyme is expressed only in CEA- producing colon-cancer cells and reverses their drug resistance selectively . Int. J. Cancer 82:346-352, 1999. (C) 1999 Wiley-Liss, Inc.