Monitoring and Targeting Anti-VEGF Induced Hypoxia within the Viable Tumor by
| Autor: | Yunzhou, Shi, Jason, Oeh, Anna, Hitz, Maj, Hedehus, Jeffrey, Eastham-Anderson, Franklin V, Peale, Patricia, Hamilton, Thomas, O'Brien, Deepak, Sampath, Richard A D, Carano |
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| Rok vydání: | 2017 |
| Předmět: |
Vascular Endothelial Growth Factor A
Original article MRI Magnetic resonance imaging Cell Survival Triazines MS Multispectral analysis Mice Nude Antineoplastic Agents Xenograft Model Antitumor Assays PFC Perfluorocarbon KM K-means TPZ Tirapazamine Fluorine-19 Magnetic Resonance Imaging Mice EC50 Half maximal effective concentration SVM Support vector machines GP Genetic programming Animals Humans Tumor Hypoxia Female R1 Spin–lattice or longitudinal relaxation rate HT29 Cells Tirapazamine VEGF-A Vascular endothelial growth factor A |
| Zdroj: | Neoplasia (New York, N.Y.) |
| ISSN: | 1476-5586 |
| Popis: | The effect of anti-angiogenic agents on tumor oxygenation has been in question for a number of years, where both increases and decreases in tumor pO2 have been observed. This dichotomy in results may be explained by the role of vessel normalization in the response of tumors to anti-angiogenic therapy, where anti-angiogenic therapies may initially improve both the structure and the function of tumor vessels, but more sustained or potent anti-angiogenic treatments will produce an anti-vascular response, producing a more hypoxic environment. The first goal of this study was to employ multispectral (MS) 19F–MRI to noninvasively quantify viable tumor pO2 and evaluate the ability of a high dose of an antibody to vascular endothelial growth factor (VEGF) to produce a strong and prolonged anti-vascular response that results in significant tumor hypoxia. The second goal of this study was to target the anti-VEGF induced hypoxic tumor micro-environment with an agent, tirapazamine (TPZ), which has been designed to target hypoxic regions of tumors. These goals have been successfully met, where an antibody that blocks both murine and human VEGF-A (B20.4.1.1) was found by MS 19F–MRI to produce a strong anti-vascular response and reduce viable tumor pO2 in an HM-7 xenograft model. TPZ was then employed to target the anti-VEGF-induced hypoxic region. The combination of anti-VEGF and TPZ strongly suppressed HM-7 tumor growth and was superior to control and both monotherapies. This study provides evidence that clinical trials combining anti-vascular agents with hypoxia-activated prodrugs should be considered to improved efficacy in cancer patients. |
| Databáze: | OpenAIRE |
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