Potent antitumor activity of IL-13 cytotoxin in human pancreatic tumors engineered to express IL-13 receptor alpha2 chain in vivo.
Interleukin-13 receptor (IL-13R) alpha2 chain plays a key role in ligand binding and internalization. We have recently demonstrated that this cytokine receptor chain has unique characteristics in tumor biology: it inhibits tumorigenicity of breast and pancreatic cancer in animal models. In this study, we have exploited IL-13Ralpha2 chain and established a novel approach for pancreatic cancer therapy. For this, a plasmid encoding the IL-13Ralpha2 chain gene was mixed with liposomes and injected into subcutaneously or orthotopically xenografted human pancreatic tumors in immunodeficient mice, followed by systemic or local therapy by a recombinant IL-13 cytotoxin. Only tumors forced to express IL-13Ralpha2 chain acquired extreme susceptibility to the antitumor effect of IL-13 cytotoxin. There was a dominant infiltration of cells including macrophages and natural killer cells in the regressing tumors. Since macrophages were found to produce nitric oxide, IL-13Ralpha2-targeted cancer therapy involved not only a direct tumor cell killing by IL-13 cytotoxin but also activation of innate immune response at the tumor site. Therefore, this approach may be a new powerful tool for pancreatic cancer or other localized cancer therapy.
Kawakami
K
K
Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, NIH Building 29, 29 Lincoln Drive, Bethesda, MD 20892-4555, USA.
Kawakami
M
M
Husain
S R
SR
Puri
R K
RK
D000818:Animals; D000951:Antigens, Neoplasm; D001665:Binding Sites; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D015552:Injections, Intralesional; D018793:Interleukin-13 / Q000276:immunology / Q000494:pharmacology*; D053661:Interleukin-13 Receptor alpha1 Subunit; D008262:Macrophage Activation; D051379:Mice; D008819:Mice, Nude; D023421:Models, Animal; D009368:Neoplasm Transplantation; D009569:Nitric Oxide / Q000096:biosynthesis; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000628:therapy*; D011869:Radioligand Assay; D018123:Receptors, Interleukin / Q000235:genetics* / Q000378:metabolism; D053660:Receptors, Interleukin-13; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection / Q000379:methods
D000951:Antigens, Neoplasm; C508181:IL13RA1 protein, human; C508183:Il13ra1 protein, mouse; D000922:Immunotoxins; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D009569:Nitric Oxide