Abstract
Background
Metastatic renal cell carcinoma (mRCC) is one of the most treatment‐resistant malignancies. Despite all new therapeutic advances, almost all patients develop resistance to treatment and cure is rarely seen. In the present study, we evaluated the antitumor effect of a bicistronic retrovirus vector encoding both endostatin (ES) and interleukin (IL)‐2 using an orthotopic metastatic RCC mouse model.
Methods
Balb/C‐bearing Renca cells were treated with NIH/3T3‐LendIRES‐IL‐2‐SN cells. In the survival studies, mice were monitored daily until they died. At the end of the in vivo experiment, serum levels of IL‐2 and ES were measured, the lung was weighed, and the number of metastatic nodules, nodule area, tumor vessels and proliferation of tumor‐infiltrating Renca cells were determined.
Results
Inoculation of NIH/3T3‐LendIRES‐IL‐2‐SN cells resulted in an increase in ES and IL‐2 levels in the treated group (p < 0.05). There was a significant decrease in lung wet weight, lung nodule area and tumor vessels in the treated group compared to the control group (p < 0.001). The proliferation of Renca cells in the bicistronic‐treated group was significantly reduced compared to the control group (p < 0.05). Kaplan–Meier survival curves showed that the probability of survival was significantly higher for mice submitted to bicistronic therapy (log‐rank test, p = 0.0016). Bicistronic therapy caused an increase in the infiltration of CD4, CD4 interferon (IFN)γ‐producing, CD8, CD8 IFNγ‐producing and natural killer (CD49b) cells.
Conclusions
Retroviral bicistronic gene transfer led to the secretion of functional ES and IL‐2 that was sufficiently active to: (i) inhibit tumor angiogenesis and tumor cell proliferation and (ii) increase the infiltration of immune cells. Copyright © 2011 John Wiley & Sons, Ltd.