title: The roles of macrophages and nitric oxide in interleukin-3-enhanced HSV-Sr39tk-mediated prodrug therapy.
abstract: The herpes simplex virus thymidine kinase/ganciclovir (HSV-sr39tk/GCV) system is a well-established prodrug system used in cancer gene therapy. However, this system is currently not effective enough to eradicate malignant tumors completely. This study aimed to evaluate whether co-expression of interleukin-3 (IL-3) could enhance the anti-tumor activity of HSV-sr39tk/GCV prodrug gene therapy using a murine TRAMP-C1 prostate tumor model. In vitro results demonstrated that HSV-sr39tk-transfected cells exhibited enhanced sensitivity to the GCV prodrug, which was not affected by co-expression of the mIL-3 gene. However, in vivo studies showed that co-expression of the mIL-3 gene significantly increased the HSV-sr39tk/GCV-induced tumor growth delay and even cured the tumor. The TRAMP-C1-specific immune response of spleen lymphocytes from mice bearing HSV-sr39tk- and IL-3-expressing TRAMP-C1 tumors was measured by ELISA. Results showed that IL-3-activated IL-4-dominant lymphocytes became IFN-γ- dominant lymphocytes after combined HSV-sr39tk/GCV therapy. The efficacy of combined therapies on tumor regression was reduced when macrophages populations were depleted by carrageenan or NO production was inhibited by administration of the iNOS inhibitor, L-NAME. These results suggest that utilizing a bicistronic vector to express HSV-sr39tk and the IL-3 gene induced an enhanced macrophage- or NO-dependent anti-tumor effect.
authors: Department of Biomedical Engineering and Environmental Sciences, National Tsing-Hua University, Hsinchu, Taiwan.
authors: Ching-Fang
authors: CF
authors: Yu
authors: Ji-Hong
authors: JH
authors: Hong
authors: Chi-Shiun
authors: CS
authors: Chiang
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D015774:Ganciclovir / Q000494:pharmacology*; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007377:Interleukin-3 / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D011355:Prodrugs; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D018139:Simplexvirus / Q000235:genetics*; D018417:Th1 Cells / Q000276:immunology; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
chemical_list: D007377:Interleukin-3; D011355:Prodrugs; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D013937:Thymidine Kinase; D015774:Ganciclovir