Tissue hypoxia results from an inadequate supply of oxygen (O₂) 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 non-invasive 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.

Tumour hyperglycolysis is driven by activation of hypoxia-inducible factor-1 (HIF-1) through tumour hypoxia. Accordingly, the degree of 2-fluro-2-deoxy-d-glucose (FDG) uptake by tumours might indirectly reflect the level of hypoxia, obviating the need for more specific radiopharmaceuticals for hypoxia imaging. In this paper, available data on the relationship between hypoxia and FDG uptake by tumour tissue in vitro and in vivo are reviewed. In pre-clinical in vitro studies, acute hypoxia was consistently shown to increase FDG uptake by normal and tumour cells within a couple of hours after onset with mobilisation or modification of glucose transporters optimising glucose uptake, followed by a delayed response with increased rates of transcription of GLUT mRNA. In pre-clinical imaging studies on chronic hypoxia that compared FDG uptake by tumours grown in rat or mice to uptake by FMISO, the pattern of normoxic and hypoxic regions within the human tumour xenografts, as imaged by FMISO, largely correlated with glucose metabolism although minor locoregional differences could not be excluded. In the clinical setting, data are limited and discordant. Further evaluation of FDG uptake by various tumour types in relation to intrinsic and bioreductive markers of hypoxia and response to radiotherapy or hypoxia-dependent drugs is needed to fully assess its application as a marker of hypoxia in the clinical setting.

This study reports on the uptake of ^99mTc-RP527 by human breast carcinoma and its relationship to gastrin-releasing peptide receptor (GRP-R) expression as measured by immunohistochemistry (IHC). Methods: Nine patients referred because of a clinical diagnosis suggestive of breast carcinoma and 5 patients with tamoxifen-resistant bone-mestastasized breast carcinoma underwent ^99mTc-RP527 scintigraphy. The findings were compared with routine staging examinations in all patients and with routine histology and IHC GRP-R staining in the first 9 patients. All 9 patients with suspected breast lesions were tumor positive. Results: The uptake of ^99mTc-RP527 was evident in the primary tumor in 8 of 9 patients and in involved lymph nodes and part of the distant metastasis limited to the bone when present. ^99mTc-RP527 uptake was not found in any of the tamoxifen-resistant patients. Conclusion: Uptake by primary breast carcinoma was significantly correlated with the presence of GRP-Rs as assessed by means of IHC.