Inhibition of angiogenesis has evolved as a promising new tool for the adjuvant treatment of various cancers. Since brain tumors are the most angiogenic neoplasms known, anti-angiogenesis might prove to be especially effective for this deadly disease. A novel antagonist of alphavbeta3 and alphavbeta5 integrins, EMD 121 974, was used in our study. This cyclic RGDfV pentapeptide inhibits neo-vascularization through irreversibly binding to the alphav-integrins of sprouting capillary vessels. Human brain tumors stereotactically xenografted into the forebrain of athymic mice responded with growth arrest and subsequent regression when treated daily with this peptide. In contrast, all animals receiving the cyclic RADfV control peptide died within 6-8 weeks from progressive tumors. We propose to expand on these findings by determining the overall survival, the length and optimal dose of peptide administration for tumor eradication, and to investigate for side effects from this peptide. Tumor growth and neo-vascularization in animals receiving the active or inactive peptide will be monitored with a novel MRI scanning technique, specifically designed for mice, and these data will be compared with histological findings. Since only orthotopically transplanted tumors (brain), but not heterotopically injected brain tumor cells (subcutis) showed growth inhibition, we propose to investigate whether the unique biochemical environment of the brain, or its capillary endothelial cells are responsible for this response. Growth and survival of capillary endothelial cells derived from the brain and subcutis, and cultured on brain specific matrix proteins will be compared in the presence and absence of RGDfV. Furthermore, the possibility of induction of direct brain tumor cell apoptosis by RGDfV will be tested by growing brain tumor cells on various matrix proteins in the presence or absence of the active peptide. In vivo studies to substantiate a direct tumoricidal effect of RGDfV on brain tumors will be with the administration of monoclonal Ab only reacting with human alphav-integrins and the use of tumors not expressing alphav-integrins. These studies will demonstrate whether the growth suppressive effect of RGDfV in brain tumors is solely due its anti-angiogenetic action or whether this peptide also has a tumoricidal effect due its prevention of interaction of brain tumor cells with brain specific matrix proteins. Overall, our data may lead to a novel, adjuvant treatment of malignant brain tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA082989-01
Application #
2904809
Study Section
Special Emphasis Panel (ZCA1-SRRB-3 (M1))
Program Officer
Wolpert, Mary K
Project Start
1999-09-30
Project End
2003-07-31
Budget Start
1999-09-30
Budget End
2000-07-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
094878337
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
Saxena, V; Gonzalez-Gomez, I; Laug, W E (2007) A non-invasive, in vivo technique for monitoring vascular status of glioblastoma during angiogenesis. Technol Cancer Res Treat 6:641-50
Saxena, Vishal; Gonzalez-Gomez, Ignacio; Laug, Walter E (2007) A noninvasive multimodal technique to monitor brain tumor vascularization. Phys Med Biol 52:5295-308
Yamada, Shinya; Bu, Xing-Yao; Khankaldyyan, Vazgen et al. (2006) Effect of the angiogenesis inhibitor Cilengitide (EMD 121974) on glioblastoma growth in nude mice. Neurosurgery 59:1304-12; discussion 1312
Chen, Xiaoyuan; Park, Ryan; Hou, Yingping et al. (2004) MicroPET imaging of brain tumor angiogenesis with 18F-labeled PEGylated RGD peptide. Eur J Nucl Med Mol Imaging 31:1081-9
Bu, Xingyao; Khankaldyyan, Vazgen; Gonzales-Gomez, Ignacio et al. (2004) Species-specific urokinase receptor ligands reduce glioma growth and increase survival primarily by an antiangiogenesis mechanism. Lab Invest 84:667-78
Chen, Xiaoyuan; Park, Ryan; Shahinian, Anthony H et al. (2004) 18F-labeled RGD peptide: initial evaluation for imaging brain tumor angiogenesis. Nucl Med Biol 31:179-89
Moats, Rex A; Velan-Mullan, Sendhil; Jacobs, Russell et al. (2003) Micro-MRI at 11.7 T of a murine brain tumor model using delayed contrast enhancement. Mol Imaging 2:150-8
Burgos, J S; Rosol, M; Moats, R A et al. (2003) Time course of bioluminescent signal in orthotopic and heterotopic brain tumors in nude mice. Biotechniques 34:1184-8
Taga, Takashi; Suzuki, Atsushi; Gonzalez-Gomez, Ignacio et al. (2002) alpha v-Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin. Int J Cancer 98:690-7
MacDonald, T J; Taga, T; Shimada, H et al. (2001) Preferential susceptibility of brain tumors to the antiangiogenic effects of an alpha(v) integrin antagonist. Neurosurgery 48:151-7

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