Molecular imaging of hypoxia with radiolabelled agents

Abstract

Tissue hypoxia results from an inadequate supply of oxygen (O 2 ) that compromises biological functions. Structural and functional abnormalities of the tumour vasculature together with altered diffusion conditions inside the tumour seem to be the main causes of tumour hypoxia. Evidence from experimental and clinical studies points to a role for tumour hypoxia in tumour propagation, resistance to therapy and malignant progression. This has led to the development of assays for the detection of hypoxia in patients in order to predict outcome and identify patients with a worse prognosis and/or patients that would benefit from appropriate treatments. A variety of invasive and noninvasive approaches have been developed to measure tumour oxygenation including oxygen-sensitive electrodes and hypoxia marker techniques using various labels that can be detected by different methods such as positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), autoradiography and immunohistochemistry. This review aims to give a detailed overview of non-invasive molecular imaging modalities with radiolabelled PET and SPECT tracers that are available to measure tumour hypoxia.Keywords Hypoxia . PET . SPECT . Nitroimidazole Hypoxia in tumour biologyThe prevalence of hypoxic areas is a characteristic feature of locally advanced solid tumours and has been described in a wide range of human malignancies, including cancer of the breast, uterine cervix, vulva, head and neck, prostate, rectum, pancreas as well as in brain tumours, soft tissue sarcomas and malignant melanomas. Up to 50-60% of locally advanced solid tumours may exhibit hypoxic and/or anoxic tissue areas that are heterogeneously distributed within the tumour mass. These hypoxic areas result from an imbalance between oxygen supply and consumption which is caused by abnormal structure and function of the microvessels supplying the tumour (causing acute hypoxia), increased diffusion distances between the nutritive blood vessels and the tumour cells (causing chronic hypoxia), and reduced O 2 transport capacity of the blood due to the presence of disease-or treatment-related anaemia [1][2][3]. Recent studies have demonstrated a clear relevance of this hypoxic microenvironment to tumour-associated metabolic alterations, which are tightly linked to the biology of the tumour. In this respect, tumour hypoxia has been associated with an aggressive tumour phenotype, poor response to radiotherapy and chemotherapy, increased risk of invasion and metastasis, and worse prognosis in advanced squamous

Hypoxia imaging predicts success of hypoxia-induced cytosine deaminase/5-fluorocytosine gene therapy in a murine lung tumor model

“…19 Moreover, the use of Tc-99m-HL91 has been described for identifying tumor hypoxia in vitro and ex vivo. 17,[19][20][21][22][23][24] The present study demonstrates for the first time, to our knowledge, that Tc99m-HL91 is useful as an imaging biomarker to predict the treatment responses of hypoxia-regulated CD/5-FC gene therapy in a mouse lung tumor model.…”

“…18 In vitro studies have identified hypoxia-selective uptake of Tc-99m-HL91, with a significant increase in the uptake in the hypoxic state compared with the normoxic state. 17,19,20 Animal studies have also shown that Tc99m-HL91 is markedly increased in mice treated with hydralazine compared with controls. 19,20 The aim of this study was to test our hypothesis that Tc-99m-HL91 imaging can be used to identify the efficacy of hypoxia-induced CD gene/5-FC gene therapy for cancer.…”

“…17,19,20 Animal studies have also shown that Tc99m-HL91 is markedly increased in mice treated with hydralazine compared with controls. 19,20 The aim of this study was to test our hypothesis that Tc-99m-HL91 imaging can be used to identify the efficacy of hypoxia-induced CD gene/5-FC gene therapy for cancer. Our results show that the tumor uptake of Tc-99m-HL91 can predict the antitumor response of the CD/5-FC cancer gene therapy.…”

Current Molecular Imaging Positron Emitting Radiotracers in Oncology

“…For instance, tirapazamine, an aromatic heterocycle di-N-oxide, is reduced to toxic radicals in hypoxic conditions and results in DNA breaks [83]. Many PET tracers have been developed to image tumor hypoxia in vivo [84][85][86][87][88]. Among them, nitroimidazole compounds are promising imaging probes to report severe hypoxia, which become reduced in a hypoxic environment and then covalently bind to intracellular macromolecules (Fig.…”

Towards Biological Target Volumes Definition for Radiotherapy Treatment Planning: Quo Vadis PET/CT?

“…The important ones include hypoxia markers (FMISO, FAZA, Cu-ATSM, and others), [66] proliferation markers (C-11-L-methionine, 2-[C-11]-thymidine, F-18-FDOPA), [67,68] necrosis marker (F-18-labeled 5-fluoropentyl-2-methyl-malonic acid), [69] apoptosis markers (4-[ 18 F]fluorobenzoylannexin V, Cu-DOTA-Annexin V), [70] and angiogenesis markers (RGD-peptides, 15 O-H 2 O) [71,72]. However, the use of these uncommon radiopharmaceuticals has been limited to a small number of academic centers, and it will take time until one of them becomes a PET marker that maps one physiological process important for the definition of a biological sub-volume.…”