A PROOF OF GLUTATHIONE S-TRANSFERASE-PI-RELATED MULTIDRUG-RESISTANCE BY TRANSFER OF ANTISENSE GENE TO CANCER-CELLS AND SENSE GENE TO BONE-MARROW STEM-CELLS

In order to directly prove the involvement of GST-pi in drug resistanc e, it's antisense gene was transduced into human colorectal cancer cel l line which has been shown to express high level of GST-pi and the se nsitivity of this cell line to anticancer drugs were assessed. The tra nsfectant showed higher sensitivity to adriamycin (3.3-fold), Cisplatn um (2.3-fold), Melphalan (2.2-fold), Etoposode (2.2-fold) than the par ental cell, while the sensitivity to vincristine, mitomicin C, 5-fluor ouracil was unchanged by transfection. When the transfectant and paren tal cells were innoculated in nude mice and treated with adriamycin, a significant suppression of tumor growth was observed with the transfe ctant as compared to the parental cell. On the basis of this observati on, we then transduced sense GST-pi gene into human bone marrow stem c ells (CD34+ cells) to protect them from toxicity of anticancer drug. T he gene transduced CD34+ cells formed more CFU-GM than nontransduced C D34+ cell in the presence of adriamycin (30 ng/ml). Thus, the autotran splantation of GST-pi gene transduced cell into cancer patients to pro tect the bone marrow from subsequent highdose chemotherapy is consider ed to be a new strategy for cancer gene therapy. (C) 1998 Elsevier Sci ence Ireland Ltd. All rights reserved.