title: Interleukin-4 cytotoxin therapy synergizes with gemcitabine in a mouse model of pancreatic ductal adenocarcinoma.
abstract: Targeting cell surface receptors with cytotoxins or immunotoxins provides a unique opportunity for tumor therapy. Here, we show the efficacy of the combination therapy of gemcitabine with an interleukin-4 (IL-4) cytotoxin composed of IL-4 and truncated Pseudomonas exotoxin in animal models of pancreatic ductal adenocarcinoma (PDA). We have observed that 42 of 70 (60%) tumor samples from patients with PDA express moderate- to high-density surface IL-4 receptor (IL-4R), whereas normal pancreatic samples express no or low-density IL-4R. IL-4 cytotoxin was specifically and highly cytotoxic [50% protein synthesis inhibition (IC50) ranging from >0.1 to 13 ng/mL] to six of eight pancreatic cancer cell lines, whereas no cytotoxicity (IC50>1,000 ng/mL) was observed in normal human pancreatic duct epithelium cells, fibroblasts, and human umbilical vein endothelial cells (HUVEC). We also showed that IL-4 cytotoxin in combination with gemcitabine exhibited synergistic antitumor activity in vitro. To confirm synergistic antitumor activity in vivo and monitor precise real-time disease progression, we used a novel metastatic and orthotopic mouse model using green fluorescent protein-transfected cancer cells and whole-body imaging system. The combination of both agents caused complete eradication of tumors in 40% of nude mice with small established PDA tumors. In addition, combined treatment significantly prolonged the survival of nude mice bearing day 14 advanced distant metastatic PDA tumors. Similar results were observed in mice xenografted with PDA obtained from a patient undergoing surgical resection. These results indicate that IL-4 cytotoxin combined with gemcitabine may provide effective therapy for the treatment of patients with PDA.
authors.affiliation: Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, NIH, Bethesda, MD 20892, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimamura
authors.forename: Richard E
authors.initials: RE
authors.lastname: Royal
authors.forename: Mitomu
authors.initials: M
authors.lastname: Kioi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakajima
authors.forename: Syed R
authors.initials: SR
authors.lastname: Husain
authors.forename: Raj K
authors.initials: RK
authors.lastname: Puri
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D015847:Interleukin-4 / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism*; D007956:Leukocidins / Q000008:administration & dosage* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000096:biosynthesis / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D007956:Leukocidins; C510238:Pseudomonas aeruginosa Cytotoxins; D019948:Receptors, Interleukin-4; D011993:Recombinant Fusion Proteins; D003841:Deoxycytidine; D049452:Green Fluorescent Proteins; D015847:Interleukin-4; D000093542:Gemcitabine