Combined therapy with direct and indirect angiogenesis inhibition results in enhanced antiangiogenic and antitumor effects

• Published in: Cancer research (Chicago, Ill.) Vol. 63; no. 24; pp. 8890 - 8898
• Main Authors: ABDOLLAHI, Amir, LIPSON, Kenneth E, HAHNFELDT, Philip, GRONE, Hermann-Josef, DEBUS, Juergen, HLATKY, Lynn, HUBER, Peter E, SCKELL, Axel, ZIEHER, Heike, KLENKE, Frank, POERSCHKE, Daniel, ROTH, Alexandra, XIAOHONG HAN, KRIX, Martin, BISCHOF, Marc
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.12.2003
• Subjects: Adenocarcinoma - blood supply; Adenocarcinoma - drug therapy; Adenocarcinoma - pathology; Angiogenesis Inhibitors - pharmacology; Animals; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - blood supply; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Cell Division - drug effects; Cell Movement - drug effects; Cell Survival - drug effects; Drug Synergism; Endostatins - pharmacology; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Female; Glioblastoma - blood supply; Glioblastoma - drug therapy; Glioblastoma - pathology; Humans; Indoles - pharmacology; Lung Neoplasms - blood supply; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Mice, SCID; Neoplasms - blood supply; Neoplasms - drug therapy; Neoplasms - pathology; Neovascularization, Pathologic - diagnostic imaging; Neovascularization, Pathologic - drug therapy; Pharmacology. Drug treatments; Prostatic Neoplasms - blood supply; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - pathology; Pyrroles - pharmacology; Tumors; Ultrasonography; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Xenograft Model Antitumor Assays; Antineoplastic agent; Angiogenesis; Inhibitor; Combined treatment
• ISSN: 0008-5472; 1538-7445

The multifaceted nature of the angiogenic process in malignant neoplasms suggests that protocols that combine antiangiogenic agents may be more effective than single-agent therapies. However it is unclear which combination of agents would be most efficacious and will have the highest degree of synergistic activity while maintaining low overall toxicity. Here we investigate the concept of combining a "direct" angiogenesis inhibitor (endostatin) with an "indirect" antiangiogenic compound [SU5416, a vascular endothelial growth factor receptor 2 (VEGFR2) receptor tyrosine kinase (RTK) inhibitor]. These angiogenic agents were more effective in combination than when used alone in vitro (endothelial cell proliferation, survival, migration/invasion, and tube formation tests) and in vivo. The combination of SU5416 and low-dose endostatin further reduced tumor growth versus monotherapy in human prostate (PC3), lung (A459), and glioma (U87) xenograft models, and reduced functional microvessel density, tumor microcirculation, and blood perfusion as detected by intravital microscopy and contrast-enhanced Doppler ultrasound. One plausible explanation for the efficacious combination could be that, whereas SU5416 specifically inhibits vascular endothelial growth factor signaling, low-dose endostatin is able to inhibit a broader spectrum of diverse angiogenic pathways directly in the endothelium. The direct antiangiogenic agent might be able to suppress alternative angiogenic pathways up-regulated by the tumor in response to the indirect, specific pathway inhibition. For future clinical evaluation of the concept, a variety of agents with similar mechanistic properties could be tested.