Chemoprotection effect of retroviral vector encoding multidrug resistance 1 gene to allow intensified chemotherapy in vivo

Abstract

Increasing the expression of human multidrug resistance (MDR) 1 gene in bone marrow cells to prevent or circumvent bone morrow toxicity from chemotherapy agent is a high priority of dose intensification protocols. In this study, we have used a tumor-bearing model to investigate the chemoprotection effect of MDR1 gene by transfecting retroviral vectors containing and expressing the MDR gene in vivo. Hematopoietic progenitor cells were served as target of MDR1 gene transferred by the mediation of retrovirus vector and engrafted into the BALB/c mice with 60Co-gamma ray exposure in advance. Doxorubicin (5, 10, and 20 mg/kg) suppressed tumor growth of the xenograft significantly in a dose-dependence mode if supported by suitable peripheral WBC. WBC count revealed that the mice that had received gene-transduced cells showed a significant increase in WBC count compared with their gene-transduced naive counterparts. The function and expression of MDR1 gene were detected by flow cytometry, RT-PCR, and immunohistochemistry (IC) method. MDRl mRNA expression could be detected in BM. Spleens contained measurable amounts of MDRl mRNA. Tail vein blood and tumor tissue detected MDRl DNA but no MDRl mRNA expression. FACS analysis of infected BM cells obtained 6 weeks later showed high levels of P-gp function. Based on these results we conclude that cytostatic drug resistance gene therapy may provide some degree of chemoprotection and so can increase the chemotherapy dose to kill tumor cells.