Sensitization of cancer cells to interleukin 13-pseudomonas exotoxin-induced cell death by gene transfer of interleukin 13 receptor alpha chain.
We have demonstrated that primary interleukin 13 (IL-13) binding protein IL-13 receptor (IL-13R) alpha chain plays an important role in IL-13 binding and internalization in the IL-13R system. Although IL-13R alpha chain is expressed on many cancer cell lines, some cancer types do not express or express low levels of this receptor chain. Consequently, these cells show no or low sensitivity to the cytotoxic effect of a recombinant chimeric protein composed of IL-13 and a mutated form of a Pseudomonas exotoxin, IL13-PE38QQR. Here we demonstrate that pancreatic cancer, renal cell carcinoma, head and neck cancer, and glioblastoma cell lines that were genetically altered to express high levels of IL-13R alpha chain increase their binding affinity for IL-13, and increase their sensitivity to IL13-PE38QQR by at least 6-fold to 1000-fold compared with mock-transfected control cells. This observation was made by protein synthesis inhibition assay and confirmed by clonogenic assay. Our studies provide a proof of principle for a novel strategy for cancer therapy that combines gene transfer and targeted cytotoxin 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, Bethesda, MD 20892, USA.
Joshi
B H
BH
Puri
R K
RK
D036002:ADP Ribose Transferases; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001427:Bacterial Toxins; D016923:Cell Death / Q000187:drug effects* / Q000235:genetics; D003114:Colony-Forming Units Assay; D005098:Exotoxins / Q000235:genetics / Q000494:pharmacology; D018014:Gene Transfer Techniques; D006801:Humans; D020128:Inhibitory Concentration 50; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D053661:Interleukin-13 Receptor alpha1 Subunit; D007457:Iodine Radioisotopes; D018123:Receptors, Interleukin / Q000187:drug effects / Q000235:genetics*; D053660:Receptors, Interleukin-13; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000970:Antineoplastic Agents; D001427:Bacterial Toxins; D005098:Exotoxins; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D007457:Iodine Radioisotopes; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D011994:Recombinant Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C508181:IL13RA1 protein, human