Specific myeloprotection via multidrug resistance 1 gene controlled by aminopeptidase N myeloid promoter

Abstract

In the treatment of tumor patients introduction of multidrug resistance genes into hematopoietic cells has been reported as an approach for reducing myelotoxicity created by antitumor drugs. However, the nonspecific expression of the genes can also increase the chemoresistance of the tumor cells invaded into bone marrow, which influences seriously the effectiveness of chemotherapy. In this study, a new strategy is described for specific myeloprotection. The recombinant retroviral vector containing multidrug resistance 1 (MDR1) gene regulated by aminopeptidase N (APN) myeloid promoter was constructed and then introduced into myeloblastic cells KG1a and tumor cell line BEL7402. The specific transcript ofMDR1 was detected in KG1a cells transduced withMDR1 gene and rhodamine 123 was effectively extruded by Pgp, the protein ofMDR1 gene. The resistance elevated markedly by 10.6, 10.4, 11.2, 4.2 and 14.2 folds inMDR1 gene-transduced KG1a cells to chemotherapeutic drugs such as cochicine, VP-16, vincristine, doxorubicin and paclitaxel, respectively. In contrast, the chemoresistance had no significant changes in BEL7402 cells transduced withMDR1 gene. Expression ofMDR1 directed byAPN myeloid promoter resulted in myelospecific protection during the killing of tumor cells treated with antitumor drugs. The study would provide a new mean for circumventing myelosuppression of tumor patients undergoing chemotherapy.