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 cancer and in normal colon tissues and has important physiological functions. In order to selectively reverse MDR in malignant tissue without disrupting the function of normal colonocytes, a retroviral vector (pCEAMR) containing anti-mdr1 ribozyme coupled to the carcino-embryonic-antigen (CEA) promoter was constructed and introduced into resistant colon-cancer cells (SW1116R) that produce CEA and into control resistant cells (HeLaK) that do not produce CEA. Anti-mdr1 ribozyme was expressed in SW1116R cells but not in HeLaK cells. Subsequently, the expression of mdr1 mRNA and Pgp decreased significantly in the transfected SW1116R cells, and was even lower than in parent non-resistant SW1116 cells. The functional ability of Pgp to facilitate rhodamine 123 (Rh123) efflux showed that the transfected SW1116R cells with low Pgp expression retained Rh123, whereas non-transfected SW1116R cells with high Pgp expression released the dye quickly. There was no difference in mdr1 mRNA or in Pgp between non-transfected and transfected HeLaK cells. Drug resistance to doxorubicin (DOX) decreased 93.1% in the transfected SW1116R cells, while no change in drug resistance occurred in the infected HeLaK cells. DOX could clearly inhibit the growth of transfected SW1116R tumors but had no effect on untransfected and on transfected HeLaK cells in vivo. These results indicate that our anti-mdr1 ribozyme is expressed only in CEA-producing colon-cancer cells and reverses their drug resistance selectively.
Gao
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TX Inc., Philadelphia, PA, USA. Gaozq@hotmail.com
Gao
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Fields
J Z
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Boman
B M
BM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000276:immunology*; D000230:Adenocarcinoma / Q000188:drug therapy*; D002272:Carcinoembryonic Antigen / Q000235:genetics; D003110:Colonic Neoplasms / Q000188:drug therapy*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009363:Neoplasm Proteins / Q000276:immunology*; D011401:Promoter Regions, Genetic; D016337:RNA, Catalytic / Q000276:immunology*; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002272:Carcinoembryonic Antigen; D009363:Neoplasm Proteins; D016337:RNA, Catalytic