Monitoring and Targeting Anti-VEGF Induced Hypoxia within the Viable Tumor by 19 F-MRI and Multispectral Analysis.

Autor: Shi Y; Department of Biomedical Imaging, Genentech Inc., South San Francisco, CA., Oeh J; Department of Translational Oncology, Genentech Inc., South San Francisco, CA., Hitz A; Department of Translational Oncology, Genentech Inc., South San Francisco, CA., Hedehus M; Department of Biomedical Imaging, Genentech Inc., South San Francisco, CA., Eastham-Anderson J; Department of Pathology, Genentech Inc., South San Francisco, CA., Peale FV Jr; Department of Pathology, Genentech Inc., South San Francisco, CA., Hamilton P; Department of Translational Oncology, Genentech Inc., South San Francisco, CA., O'Brien T; Department of Translational Oncology, Genentech Inc., South San Francisco, CA., Sampath D; Department of Translational Oncology, Genentech Inc., South San Francisco, CA., Carano RAD; Department of Biomedical Imaging, Genentech Inc., South San Francisco, CA. Electronic address: carano.richard@gene.com.
Jazyk: angličtina
Zdroj: Neoplasia (New York, N.Y.) [Neoplasia] 2017 Nov; Vol. 19 (11), pp. 950-959. Date of Electronic Publication: 2017 Oct 06.
DOI: 10.1016/j.neo.2017.07.010
Abstrakt: 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 pO 2 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) 19 F-MRI to noninvasively quantify viable tumor pO 2 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 19 F-MRI to produce a strong anti-vascular response and reduce viable tumor pO 2 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.
(Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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