Administering plasmid DNA encoding tumor vessel-anchored IFN-alpha for localizing gene product within or into tumors.
Tumor-targeted gene delivery has been intensively studied in the field of gene therapy, but no attention has been given to targeting the therapeutic gene products, which are transcribed and translated from the injected genes, into tumors. Targeting immune stimulatory gene products into tumors is the key to triggering tumor-specific CD8(+) T-cell responses and reducing systemic toxicity. To target the gene products generated from the injected genes into tumors, genes encoding the tumor-targeted fusion gene product were generated and administered locally and systemically via electroporation. As anticipated, administration of a therapeutic gene encoding IFN-alpha and the tumor vessel-targeted peptide CDGRC fusion gene product minimizes the leakage of immunostimulatory cytokine from tumors into the blood circulation, increases the infiltration of CD8(+) T cells into tumors, induces a high magnitude of cytotoxic T-cell lysis (CTL) activity, and reduces tumor vessel density. As a result, tumor growth was more significantly inhibited by administering the IFN-alpha-CDGRC gene than by administering the wild-type IFN-alpha gene. The same result was obtained with the systemic administration of the tumor-targeted IFN-alpha gene. This gene product-based tumor-targeted gene therapy approach could complement any other tumor-targeted gene delivery method for improving tumor-targeting efficiency.
Craig
Ryan
R
Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge, Louisiana 70803, USA.
Cutrera
Jeffry
J
Zhu
Shiguo
S
Xia
Xueqing
X
Lee
Yong-Hwan
YH
Li
Shulin
S
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D018826:CD13 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D004247:DNA / Q000737:chemistry*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D016898:Interferon-alpha / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D010957:Plasmids / Q000378:metabolism*
D016898:Interferon-alpha; D004247:DNA; D018826:CD13 Antigens