This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rakhmilevich, A. L. Articles by Sondel, P. M. Search for Related Content PubMed PubMed Citation Articles by Rakhmilevich, A. L. Articles by Sondel, P. M.

¹ University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin and ² ImClone Systems, Inc., New York, New York

Requests for reprints: Alexander L. Rakhmilevich, K4/413 Clinical Science Center, Department of Human Oncology, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI 53792. Phone: 608-263-5193; Fax: 608-263-4229. E-mail: rakhmil{at}humonc.wisc.edu

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 2/ 4/04; revised 4/19/04; accepted 6/10/04.

This article has been cited by other articles:

				S. Zhu, M. Waguespack, S. A. Barker, and S. Li Doxorubicin Directs the Accumulation of Interleukin-12 Induced IFN{gamma} into Tumors for Enhancing STAT1 Dependent Antitumor Effect Clin. Cancer Res., July 15, 2007; 13(14): 4252 - 4260. [Abstract] [Full Text] [PDF]

				S. Lee, J. Mandic, and K. J. Van Vliet From the Cover: Chemomechanical mapping of ligand-receptor binding kinetics on cells PNAS, June 5, 2007; 104(23): 9609 - 9614. [Abstract] [Full Text] [PDF]

				M. N. Torrero, X. Xia, W. Henk, S. Yu, and S. Li Stat1 deficiency in the host enhances interleukin-12-mediated tumor regression. Cancer Res., April 15, 2006; 66(8): 4461 - 4467. [Abstract] [Full Text] [PDF]

				V. Askoxylakis, S. Zitzmann, W. Mier, K. Graham, S. Kramer, F. von Wegner, R. H.A. Fink, M. Schwab, M. Eisenhut, and U. Haberkorn Preclinical Evaluation of the Breast Cancer Cell-Binding Peptide, p160 Clin. Cancer Res., September 15, 2005; 11(18): 6705 - 6712. [Abstract] [Full Text] [PDF]