Abstract
Interleukin 3 (IL-3) is a hematopoietic factor and can stimulate stem cell proliferation and differentiation. In previous studies, IL-3 transduced tumors grow slower than parental tumors in vivo. Besides, IL3 could enhance CTL generation to exogenous antigen and then suppress metastatic cancer. Therefore, IL-3 gene therapy will be a potential approach for treatment of cancer. However, the large amount of IL-3 expression in host will result in systemic side effect. In this study, I will establish an inducible adenovirus IL-3 gene expression system for prostate cancer therapy. The adenovirus Tet-on system (BD) was used as gene vector to deliver IL-3 gene to tumor cell. The advantage of Tet-on system is that the inserted gene can be regulated by doxycycline (Dox) to reduce the risk of gene therapy. Moreover, the intratumoral expression of IL-3 by adenovirus can concentrate the IL-3 protein inside tumor and was more effective in enhancing the IL-3 elicited tumor-specific cellular immunity. The expression level of IL-3 depends on the concentration of Dox both in vitro and in vivo. In this study, two procedures were used to deliver Dox to the target in vivo. The results demonstrated that it is more efficient to deliver the Dox by Alzet osmotic pump than by drinking water uptake. This effect was further reflected in a longer tumor growth delay. The antitumor effect of IL-3 was evaluated in a mouse mode of prostate cancer (TRAMP C-1). During the early stage of tumor development, IL-3 treated tumors displayed a slower growth rate compared with control tumors. The expression of IL-3 within tumors increased the amount of tumor-infiltrating lymphocytes (TILs). However, this effect was not able to induce enough CTL response to reject the tumor. It is therefore suggested to combine this system with others, such as radiation therapy, for treatment of prostate cancer.