Evidence that IL-13R alpha2 chain in human glioma cells is responsible for the antitumor activity mediated by receptor-directed cytotoxin therapy.
The interleukin-13 receptor alpha2 (IL-13R alpha2) chain is a primary IL-13 binding and internalization component of the IL-13R system. Previous studies have shown that human brain tumors, including glioblastoma multiforme (GBM), overexpress IL-13R alpha2 chain, while normal brain cells do not express this protein or express very low levels of it. To target IL-13R on brain tumor cells, the authors have developed an IL-13R-directed cytotoxin termed IL13-PE38QQR to induce specific cancer cell killing. To investigate the role of IL-13R alpha2 chain in GBM, cells were treated with antisense oligonucleotide or siRNA to IL-13R alpha2 chain, and cellular IL-13 binding and sensitivity to IL-13 cytotoxin were assessed. IL-13R alpha2 gene interference in GBM cells showed decreased ligand binding, and consequently IL-13 cytotoxin exhibited less cytotoxicity to these cells. The authors next evaluated the antitumor activity of IL-13 cytotoxin in native IL-13R-expressing tumors and after gene transfer of IL-13R alpha2 by injecting plasmid in U87MG tumors subcutaneously implanted in nude mice. These mice were then treated with IL-13 cytotoxin. Mean tumor size in mice receiving intraperitoneal or intratumoral IL-13 cytotoxin was significantly smaller in control tumors; however, tumor sizes were much smaller in IL-13R alpha2-transfected tumors. Furthermore, convection-enhanced delivery of IL-13R alpha2 cDNA in intracranially established U87MG glioma followed by IL-13 cytotoxin administration by the same route mediated tumor regression and prolonged survival of animals by 164% compared with control. These results indicate that IL-13R alpha2 chain in GBM cells is essential for IL-13 cytotoxin-induced cytotoxicity and that IL-13R alpha2 chain plays a critical biologic role in IL-13 cytotoxin-mediated therapy for GBM.
Kawakami
Koji
K
Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
Kioi
Mitomu
M
Liu
Qi
Q
Kawakami
Mariko
M
Puri
Raj K
RK
D000818:Animals; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics; D005098:Exotoxins; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D018793:Interleukin-13 / Q000627:therapeutic use*; D053661:Interleukin-13 Receptor alpha1 Subunit; D051379:Mice; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D053660:Receptors, Interleukin-13; D011993:Recombinant Fusion Proteins; D023041:Xenograft Model Antitumor Assays
D005098:Exotoxins; C521502:IL13-PE38; C508181:IL13RA1 protein, human; C508183:Il13ra1 protein, mouse; D000922:Immunotoxins; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D034741:RNA, Small Interfering; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D011993:Recombinant Fusion Proteins