Treatment of experimental breast cancer using interleukin-12 gene therapy combined with anti-vascular endothelial growth factor receptor-2 antibody.

Abstract

We have shown previously that interleukin-12 (IL-12) gene therapy induced strong antitumor effects in several syngeneic murine tumor models including 4T1 mammary adenocarcinoma. Antiangiogenic treatment with a monoclonal antibody (mAb) directed against the vascular endothelial growth factor receptor-2 (VEGFR-2) is another promising treatment approach that can cause transient suppression of tumor growth. We hypothesized that the combination of IL-12 gene therapy and anti-VEGFR-2 mAb will achieve better antitumor and antimetastatic effects against 4T1 adenocarcinoma than each treatment alone via implementation of different mechanisms. Administration of anti-VEGFR-2 mAb into BALB/c mice bearing s.c. 4T1 tumors induced significant suppression of tumor growth, as did intratumoral administration of naked IL-12 DNA. The combined treatment with anti-VEGFR-2 mAb and IL-12 DNA resulted in significantly enhanced inhibition of tumor growth as compared with each treatment alone. This combination was also effective against spontaneous lung metastases. In T-cell-deficient nude mice, both IL-12 DNA and anti-VEGFR-2 mAb were effective in suppressing tumor growth. In T-cell- and natural killer cell-deficient scid/beige mice, only anti-VEGFR-2 mAb was effective, suggesting that natural killer cells are involved in the antitumor effects induced by IL-12 DNA. In both types of immunodeficient mice, the combination of anti-VEGFR-2 mAb and IL-12 DNA was as effective in suppressing 4T1 tumor growth as anti-VEGFR-2 mAb alone. Antitumor effects of anti-VEGFR-2 mAb were associated with the inhibition of angiogenesis within the tumors, whereas the antiangiogenic effect of IL-12 gene therapy was not detected. Our results show a therapeutic benefit of combining IL-12 gene therapy and anti-VEGFR-2 mAb for cancer treatment.

• Authors: Alexander L Rakhmilevich, Andrea T Hooper, Daniel J Hicklin, Paul M Sondel
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 3 Issue 8 Pg. 969-76 (Aug 2004) ISSN: 1535-7163 [Print] United States
• PMID: 15299079 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Angiogenesis Inhibitors
• Antibodies
• Antibodies, Monoclonal
• Antineoplastic Agents
• Interleukin-12
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antibodies (chemistry)
• Antibodies, Monoclonal (chemistry)
• Antineoplastic Agents (pharmacology)
• Dose-Response Relationship, Drug
• Genetic Therapy (methods)
• Interleukin-12 (genetics, metabolism)
• Mammary Neoplasms, Animal (genetics, therapy)
• Mammary Neoplasms, Experimental (genetics, therapy)
• Mice
• Mice, Inbred BALB C
• T-Lymphocytes (metabolism)
• Time Factors
• Vascular Endothelial Growth Factor Receptor-2 (genetics, immunology)