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Interleukin 4 receptor on human lung cancer: a molecular target for cytotoxin therapy
Mariko Kawakami1, Koji Kawakami, Vitaly A Stepensky
1Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
Abstract:
Previous studies have demonstrated that human lung tumor cell lines express interleukin 4 (IL-4) receptors, and IL-4 can mediate modest to moderate antiproliferative activity in vitro and in vivo in animal models of human lung tumors. On the basis of these studies, IL-4 was tested in clinical trials; however, it showed little antitumor activity in lung cancer patients. In the present study, we examined the expression of IL-4 receptors (IL-4Rs) in lung tumor samples and normal lung tissues and tested whether an IL-4R targeted agent will have better antitumor activity in vitro and in vivo compared with IL-4. IL-4R expression was tested by immunohistochemistry in 54 lung tumor samples and normal lung tissues in a tissue array, by reverse-transcription PCR and Northern blot analyses in lung tumor cell lines. Cytotoxic activity of IL-4 cytotoxin [IL-4(38-37)-PE38KDEL], composed of a circular permuted IL-4 and a mutated form of Pseudomonas exotoxin (PE38KDEL) was tested by protein synthesis inhibition and clonogenic assays in seven lung tumor cell lines. Antitumor activity of IL-4 cytotoxin was tested in vitro and in immunodeficient animal models of human lung tumors. We observed that IL-4Rs are expressed at higher levels in situ in lung tumor samples compared with normal lung tissues and IL-4 cytotoxin is highly and specifically cytotoxic to lung tumor cell lines in vitro. Intratumoral and i.p. administration of IL-4 cytotoxin to immunodeficient mice with s.c. established human lung H358 non-small cell lung cancer tumors mediated considerable antitumor activity in a dose-dependent manner with the higher dose producing durable complete responses. On the other hand, H460 non-small cell lung cancer tumors expressing low levels of IL-4R did not respond to IL-4 cytotoxin therapy. Because IL-4 cytotoxin mediates its antitumor activity through IL-4R, and a variety of lung tumors expressed high levels of IL-4R, we propose testing the safety of this agent in patients with lung cancer.
Insights
Interleukin-4 receptors (IL-4Rs) are more prevalent in lung tumors than normal tissue. An IL-4R-targeted cytotoxin demonstrated significant antitumor activity in preclinical models, suggesting potential for lung cancer treatment.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Interleukin-4 (IL-4) showed limited efficacy in lung cancer clinical trials despite preclinical promise.
- IL-4 receptors (IL-4Rs) are expressed on human lung tumor cells, but their role in therapeutic response is unclear.
Purpose of the Study:
- To investigate IL-4R expression in lung tumors versus normal lung tissue.
- To evaluate the efficacy of an IL-4R-targeted cytotoxin compared to IL-4 for lung cancer treatment.
Main Methods:
- Immunohistochemistry, RT-PCR, and Northern blot analysis were used to assess IL-4R expression.
- In vitro cytotoxicity assays and in vivo studies in immunodeficient mice models were performed using IL-4 cytotoxin.
Main Results:
- IL-4Rs were significantly upregulated in lung tumor samples compared to normal lung tissues.
- IL-4 cytotoxin exhibited potent and specific cytotoxicity against lung tumor cell lines in vitro.
- In vivo, IL-4 cytotoxin demonstrated dose-dependent antitumor activity, achieving complete responses in some models.
Conclusions:
- IL-4R expression is higher in lung tumors, making them potential targets for IL-4R-based therapies.
- IL-4 cytotoxin shows promising preclinical efficacy and warrants further investigation in lung cancer patients.