Regression of human mammary adenocarcinoma by systemic administration of a recombinant gene encoding the hFlex-TRAIL fusion protein.
The tumor necrosis factor (TNF)-related apoptosis-inducing ligand, TRAIL, is a new member of the TNF family. It can specifically induce apoptosis in a variety of human tumors. To investigate the possibility of employing the TRAIL gene for systemic cancer therapy, we constructed a recombinant gene encoding the soluble form of the human Flt3L gene (hFlex) at the 5' end and the human TRAIL gene at the 3' end. Such design allows the TRAIL gene product to be secreted into the body circulation. We have also demonstrated that the addition of an isoleucine zipper to the N-terminal of TRAIL greatly enhanced the trimerization of the fusion protein and dramatically increased its anti-tumor activity. The fusion protein reached the level of 16-38 microg/ml in the serum after a single administration of the recombinant gene by hydrodynamic-based gene delivery in mice. A high level of the fusion protein correlated with the regression of a human breast tumor established in SCID mice. No apparent toxicity was observed in the SCID mouse model. In addition, the fusion protein caused an expansion of the dendritic cell population in the C57BL/6 recipient mice, indicating that the hFlex component of the fusion protein was functional. Thus, the hFlex-TRAIL fusion protein may provide a novel approach, with the possible involvement of dendritic cell-mediated anti-cancer immunity, for the treatment of TRAIL-sensitive tumors.
Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
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D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D051379:Mice; D016513:Mice, SCID; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000097:blood / Q000627:therapeutic use; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C084881:flt3 ligand protein