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.
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