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.
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.
Koji
K
Kawakami
Mariko
M
Kawakami
Syed R
SR
Husain
Raj K
RK
Puri
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