This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Cline, E. I. Articles by Lingen, M. W. Search for Related Content PubMed PubMed Citation Articles by Cline, E. I. Articles by Lingen, M. W.

Prediction of in Vivo Synergistic Activity of Antiangiogenic Compounds by Gene Expression Profiling¹

The Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, Illinois 60153 [E. I. C.]; Department of Chemical Process Engineering, University of Padova, Italy 35131 [S. B., C. D.]; and Department of Pathology, Division of Biological Sciences, Department of Pathology, The University of Chicago, Chicago, Illinois 60637 [M. W. L.]

Angiogenesis, an essential phenotype for tumor formation, requires the interaction of many cells within the tumor microenvironment. Therefore, successful antiangiogenic therapies must be ableZ to block all of the different mechanisms tumors use to induce neovascularization. A major challenge for developing such protocols is determining which agents are likely to have the highest degree of synergistic activity in vivo. We treated human microvascular endothelial cells with six inhibitors of angiogenesis and used microarrays to seek divergent patterns of gene expression suggestive of potential synergies. The expression profiles of a thrombospondin-mimetic peptide (DI-TSPa) and TNP-470 (TNP) were very similar, whereas endostatin had a dramatically different profile. In vitro, endostatin was synergistically antiangiogenic with either TNP-470 or DI-TSPa. In vivo, mice bearing Lewis lung carcinoma cells treated with a combination of endostatin and either DI-TSPa or TNP-470, at doses that were ineffective when used alone, resulted in a marked inhibition of tumor growth and decreased tumor angiogenesis. Conversely, animals treated with both DI-TSPa and TNP-470 demonstrated a modest effect on both tumor growth and angiogenesis. These results suggest that even in the absence of a complete mechanistic understanding of how these inhibitors work, gene expression profiling may be used to predict synergistic antiangiogenic activity and thus maximize their antitumor efficacy.

This article has been cited by other articles:

				J. Hong, R. C. Doebele, M. W. Lingen, L. A. Quilliam, W.-J. Tang, and M. R. Rosner Anthrax Edema Toxin Inhibits Endothelial Cell Chemotaxis via Epac and Rap1 J. Biol. Chem., July 6, 2007; 282(27): 19781 - 19787. [Abstract] [Full Text] [PDF]

				K. Yano, K. Imai, A. Shimizu, and T. Hanashita A new method for gene discovery in large-scale microarray data Nucleic Acids Res., March 14, 2006; 34(5): 1532 - 1539. [Abstract] [Full Text] [PDF]