Chemoprotection Effect of Multidrug Resistance 1 (MDR1) Gene Transfer to Hematopoietic Progenitor Cells and Engrafted in Mice with Cancer Allows Intensified Chemotherapy

Abstract

Increasing the proportion of bone marrow cells expression human multidrug resistance (MDR) 1 gene 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 BALB/c mouse 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 served as a target of MDR1 gene transfer by the mediation of retrovirus vector and engrafted into the BALB/c mice with 60Co-γ ray exposure in advance. Doxorubicin (5, 10, and 20 mg/kg) suppressed tumor growth of the xenograft significantly in dose-dependence mode if supported by suitable peripheral WBC. WBCs count revealed that the mice that had received gene-transduced cells showed a significant increase in WBCs 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 so can increase the chemotherapy dose to kill tumor cells.

Keywords:

• Gene therapy
• Multidrug resistance
• P-glycoprotein
• Marrow transplant