Neovascular Targeting with Cyclic RGD Peptide (cRGDf-ACHA) to Enhance Delivery of Radioimmunotherapy
| Autor: | Kathleen R. Lamborn, Patricia A. Burke, Laird Miers, Sally J. DeNardo, Siegfried Matzku, Alfred Jonczyk, Linda A. Kroger, Gerald L. DeNardo, Simon L. Goodman, Bryan R. Leigh, Robert T. O'Donnell |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Cancer Research
medicine.medical_specialty Alpha-v beta-3 Arginine Metabolic Clearance Rate medicine.drug_class medicine.medical_treatment Mice Nude Angiogenesis Inhibitors Breast Neoplasms Vascular permeability Adenocarcinoma Pharmacology Monoclonal antibody Peptides Cyclic Pentapeptide repeat Mice chemistry.chemical_compound Heterocyclic Compounds Internal medicine Tumor Cells Cultured medicine Animals Humans Radiology Nuclear Medicine and imaging Neovascularization Pathologic biology Indium Radioisotopes Antagonist General Medicine Radioimmunotherapy Combined Modality Therapy Endocrinology Oncology chemistry biology.protein Female Vitronectin Radiopharmaceuticals Oligopeptides |
| Zdroj: | Cancer Biotherapy and Radiopharmaceuticals. 15:71-79 |
| ISSN: | 1557-8852 1084-9785 |
| DOI: | 10.1089/cbr.2000.15.71 |
| Popis: | Radioimmunotherapy (RIT) has been hampered by delivery of only a small fraction of the administered dose of radiolabeled MAb to tumor. A strategy for creating and controlling tumor vascular permeability would enable more effective RIT. The alpha v beta 3 integrin receptor is an appealing target for strategies designed to enhance permeability of tumor vessels because it is highly and preferentially expressed in most tumors. In human tumor mouse models, apoptosis of neovascular endothelial cells has been demonstrated after treatment with alpha v beta 3 antagonists. Since this apoptotic effect could transiently increase permeability of tumor blood vessels, radiolabeled antibodies (MAb) circulating during this period would have increased access to extravascular tumor. To determine if this hypothesis was correct, a pharmacokinetic study of an immunospecific MAb given after an alpha v beta 3 antagonist was performed in nude mice bearing human breast cancer xenografts. The alpha v beta 3 antagonist, cyclic RGD pentapeptide (c-RGDf-ACHA; cyclo arginine glycine aspartic acid D-phenylalanine -1 amino cyclohexane carboxylic acid), inhibits alpha v beta 3 binding to its vitronectin ligand at nanomolar levels. Cyclic RGD peptide (250 micrograms i.p.) given 1 hour before 111In-ChL6 MAb resulted in a 40-50% increase in tumor uptake (concentration), when compared to the control tumor uptake, of MAb 24 hours after administration. When cyclic RGD peptide was given as a continuous infusion (17.5 micrograms/hr) for 1 or 24 hours before 111In-ChL6, tumor uptake of 111In-ChL6 was increased less, and, these data were not statistically different from the control data. There were no differences for any of the groups in the groups in the concentrations of 111In-ChL6 in normal organs or blood when compared to the control group. The results suggest that cyclic RGD peptide provided a temporary, selective increase in tumor vascular permeability, that allowed a larger fraction of the 111In-ChL6 to accumulate in the tumor. |
| Databáze: | OpenAIRE |
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