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Synergistic anti‐tumor effect of glycosylphosphatidylinositol‐anchored IL‐2 and IL‐12
Author(s) -
Ji Jianfei,
Li Jinhua,
Holmes Lillia M.,
Burgin Kelly E.,
Yu Xianzhong,
Wagner Thomas E.,
Wei Yanzhang
Publication year - 2004
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.547
Subject(s) - cytokine , immune system , transfection , melanoma , cancer research , in vivo , interleukin , interleukin 2 , immunology , cell culture , medicine , biology , microbiology and biotechnology , genetics
Background Preclinical and clinical studies have demonstrated that interleukin 2 (IL‐2), interleukin 12 (IL‐12), and some other cytokines, play important roles in activating host immune responses against tumor growth. However, severe side effects caused by systemic high‐dose administration of these cytokines limit their clinical application. In our previous study, local high doses of IL‐2 were achieved by a GPI‐anchoring technology; therefore, it will be interesting to know if this technology works for other cytokines. Methods A fusion gene containing murine IL‐12 and the glycosylphosphatidylinositol (GPI) anchor signal sequence was generated and transfected into the murine melanoma tumor cell line B16F0 either alone or together with a vector encoding GPI‐anchored IL‐2. The GPI‐anchored cytokine expression of the selected stable clones was assayed in vitro by ELISA and their anti‐tumor effects were analyzed in vivo by tumor lymphocyte infiltration and tumor growth studies. Results GPI‐anchored IL‐12 was successfully expressed on the cell surface as indicated by FACS analysis and IL‐12 ELISA assay. The GPI‐anchored IL‐12 enhanced lymphocyte infiltration and significantly inhibited tumor growth. More importantly, when GPI‐anchored IL‐12 and GPI‐anchored IL‐2 were co‐delivered, a synergistic anti‐tumor effect was observed in both subcutaneous and intravenous tumor models. Conclusions GPI anchorage of cytokines represents a new approach to locally deliver high doses of cytokines without the severe adverse effects normally accompanied with systematic high‐dose administration of these cytokines. Copyright © 2004 John Wiley & Sons, Ltd.