Effect of interleukin (IL)-4 cytotoxin on breast tumor growth after in vivo gene transfer of IL-4 receptor alpha chain

Clin Cancer Res. 2003 May;9(5):1826-36.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm
  • Antineoplastic Agents / immunology
  • Antineoplastic Agents / pharmacology
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Gene Transfer Techniques
  • Genetic Therapy / methods*
  • Humans
  • Immunotoxins / pharmacology*
  • Injections, Intralesional
  • Interleukin-4 / immunology
  • Interleukin-4 / pharmacology*
  • Macrophage Activation
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / therapy*
  • Mice
  • Mice, Nude
  • Radioligand Assay
  • Receptors, Interleukin-4 / genetics*
  • Receptors, Interleukin-4 / metabolism
  • Tumor Cells, Cultured / transplantation


  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Immunotoxins
  • Receptors, Interleukin-4
  • Interleukin-4