The effect of imatinib therapy on tumour cycling hypoxia, tissue oxygenation and vascular reactivity

Miguel R Gonçalves,Sean Peter Johnson,Rajiv Ramasawmy,R Barbara Pedley,Simon Walker-Samuel,Mark F Lythgoe

doi:10.12688/wellcomeopenres.11715.1

Abstract

Background: Several biomedical imaging techniques have recently been developed to probe hypoxia in tumours, including oxygen-enhanced (OE) and blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI). These techniques have strong potential for measuring both chronic and transient (cycling) changes in hypoxia, and to assess response to vascular-targeting therapies in the clinic. Methods: In this study, we investigated the use of BOLD and OE-MRI to assess changes in cycling hypoxia, tissue oxygenation and vascular reactivity to hyperoxic gas challenges, in mouse models of colorectal therapy, following treatment with the PDGF-receptor inhibitor, imatinib mesylate (Glivec). Results: Whilst no changes were observed in imaging biomarkers of cycling hypoxia (from BOLD) or chronic hypoxia (from OE-MRI), the BOLD response to carbogen-breathing became significantly more positive in some tumour regions and more negative in other regions, thereby increasing overall heterogeneity. Conclusions: Imatinib did not affect the magnitude of cycling hypoxia or OE-MRI signal, but increased the heterogeneity of the spatial distribution of BOLD MRI changes in response to gas challenges.

Highlights

Changes in tumour blood oxygen saturation, blood flow and tissue oxygen concentration can each be detected noninvasively via recent advances in magnetic resonance imaging (MRI)
Cycling hypoxia has been found to contribute to therapeutic resistance by limiting tumour drug delivery16 or, alongside chronic hypoxia, by lowering oxygen concentration
Assessment of tumour growth rate Administration of imatinib did not significantly affect the growth rate of LS174T tumours, as assessed by both MRI and calliper measurements. This is consistent with previous studies in the same tumour type18, changes were observed on histology

Summary

Introduction

Changes in tumour blood oxygen saturation, blood flow and tissue oxygen concentration can each be detected noninvasively via recent advances in magnetic resonance imaging (MRI). Blood oxygen level dependent (BOLD) MRI allows changes in tumour deoxyhaemoglobin concentration to be detected and oxygen-enhanced (OE) MRI uses the change in longitudinal relaxation time to detect changes in oxygen concentration in tissue, resulting from inhalation of a hyperoxic gas2,3 Using these biomedical techniques, alongside others, it has been found that numerous solid tumours exhibit cyclical variations in blood flow and/or oxygenation, resulting in cycling hypoxia in tumour tissue, with a period of minutes to hours or even days. Several biomedical imaging techniques have recently been developed to probe hypoxia in tumours, including oxygen-enhanced (OE) and blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) These techniques have strong potential for measuring both chronic and transient (cycling) changes in hypoxia, and to assess response to vascular-targeting therapies in the clinic. Conclusions: Imatinib did not affect the magnitude of cycling hypoxia or OE-MRI signal, but increased the heterogeneity of the spatial distribution of BOLD MRI changes in response to gas challenges.

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