Studies On Drug-and Radiation-Resistance Genes Regulated By Myeloid-Specific Promoter

Multidrug resistance 1 (MDR1) and maganese superoxide dismutase(MnSOD) have been applied to reduce myelotoxicty induced by antitumor drugs and/or radiation. However, this approach conferred the resistance to not only myelopoietic cells but also tumor cells that have invaded or metastasized into bone marrow or circulating blood for nonspecific expression of the exogenous genes. In this study, a new strategy was described for selective expression of MDR.1 gene and MnSOD gene and specific protection of myeloid cells from chemotherapeutic drugs and radiation without dramatically enhancing the resistance of tumor cells.Luciferase reporter analysis revealed that aminopeptidase N (APN) upstream promoter extending from -411 to +65 was myelo-specific, which exhibited high activity in myeloid cells and low activity in T acute lymphoid leukemia cells, lung adenoma cells, tong carcinoma cells, esophageal carcinoma cells, and especially hepatoma cells.Basing on the results of the reporter gene assay, MDR1 gene and MnSOD gene regulated by APN myeloid promoter in retroviral vectors were introduced into hematopoietic cell line KGla and hepatoma cell line BEL7402. The level of expression and the biochemical activity of MDR1 and MnSOD increased in KG1a cell line transduced with MDR1 gene and MnSOD gene. The resistance...