Effect of interleukin (IL)-4 cytotoxin on breast tumor growth after in vivo gene transfer of IL-4 receptor alpha chain.
Although human breast cancer cells express interleukin-4 receptors (IL-4Rs), a recombinant fusion protein, IL-4 cytotoxin, did not mediate desirable antitumor activity in tumor models of breast cancer. Recent studies have identified that a primary IL-4 binding protein, IL-4Ralpha chain, is internalized after binding to IL-4 in cancer cells. The consequent expression of high-level IL-4Ralpha in tumor cells sensitizes them to the cytotoxic effect of IL-4 cytotoxin in vitro. To assess whether overexpression of IL-4Ralpha chain in vivo by plasmid-mediated gene transfer can enhance antitumor activity of IL-4 cytotoxin in mouse models of breast tumor, we injected MDA-MB-231 human breast cancer cells in both flanks of athymic nude mice. Animals then received three intratumoral (i.t.) injections of either IL-4Ralpha encoding vector (left flank) or vector only (right flank) mixed with liposome followed by IL-4 cytotoxin administration. Both i.p. and i.t. administration of IL-4 cytotoxin profoundly reduced the growth of IL-4Ralpha plasmid-injected MDA-MB-231 tumors, compared with control. Innate immune cells, including macrophages and neutrophils, were found to infiltrate at the regressing tumor site. This study provides proof of principle that i.t. IL-4Ralpha plasmid injection followed by systemic or i.t. IL-4 cytotoxin administration may be a useful strategy for the treatment of breast cancer.
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.
Kawakami
Mariko
M
Husain
Syed R
SR
Puri
Raj K
RK
D000818:Animals; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D015552:Injections, Intralesional; D015847:Interleukin-4 / Q000276:immunology / Q000494:pharmacology*; D008262:Macrophage Activation; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D011869:Radioligand Assay; D019948:Receptors, Interleukin-4 / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000637:transplantation
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D000922:Immunotoxins; D019948:Receptors, Interleukin-4; D015847:Interleukin-4