Review of Positron Emission Tomography Tracers for Imaging of Tumor Hypoxia

Abstract

Hypoxia plays a critical role in tumor development and aggressiveness and is an important prognostic factor for resistance to antineoplastic treatments; therefore, it is required to measure the hypoxic level of tumor for a favorable outcome. The pretherapy information on the oxygenation status of a tumor microenvironment should also have implications for treatment selection. A diffuse distribution of hypoxia in a tumor might suggest a benefit from a systemic approach, such as a hypoxic cell cytotoxin, tirapazamine, or antigrowth factor drugs to combat the limitations of hypoxia. Alternatively, a more focal hypoxia might benefit from a local/regional approach, such as intensity-modulated radiation therapy-based radiation dose escalation to the hypoxic subvolume. This review anticipates that (18)F-FMISO ((18)F-fluoromisonodazole) and (64)Cu-ATSM-positron emission tomography (PET) will prove useful for selecting individual patients for the most appropriate treatment. The advent of new radiotracers has allowed noninvasive assessment of hypoxia, with the most extensively investigated and validated PET radiotracer for hypoxia to date being (18)F-FMISO. This article discusses the relevance and biology of hypoxia in cells and organ systems and reviews the laboratory and clinical applications of (18)F-FMISO and other agents in oncology.

The HIF-1α Hypoxia Response in Tumor-Infiltrating T Lymphocytes Induces Functional CD137 (4-1BB) for Immunotherapy

“…Hence, the alternative hypothesis of indirect CD137 enhancing effects mediated by genes upregulated by the transcriptional activity of HIF-1α is under investigation. In fact, previous reports have revealed a functional interplay of HIF-1α and NF-κB members (44), whereas canonical NF-κB sites are leading inducers of the CD137 promoter (10). In fact, CD137 upregulation in our experiments seems to take place mainly at the transcriptional level.…”

“…First, we found that in tumors in which we detect CD137 + , TILs are indeed undergoing hypoxia as documented on living mice by sensitive 18 F-MISO positron emission tomographic (PET) imaging based on imidazole chemistry (10). This property applies both to transplanted (CT26, MC38, B16-OVA) and spontaneous tumors ( Supplementary Fig.…”

Characterization of Different Osteosarcoma Phenotypes by PET Imaging in Preclinical Animal Models

“…Franzius et al reported no differences in tumor uptake among the subtypes of the conventional-type osteosarcoma-that is, osteoblastic, fibroblastic, and chondroblastichowever, no reports are found evaluating possible differences in 18 F-FDG uptake among the different types of osteosarcoma (12). 18 F-FMISO is an indicator of hypoxia that diffuses passively into cells and is retained only in hypoxic areas after a 2-electron reduction reaction (13). It is well established that hypoxia is associated with aggressive tumor phenotype and with pronounced chemoresistance dependent on the higher expression and stabilization of the heterodimeric hypoxia-inducible factor complex and on the overexpression of direct targets such as carbonic anhydrase IX (CaIX), which is associated with worse prognosis and lower survival in several tumors (13,14).…”

“…18 F-FMISO is an indicator of hypoxia that diffuses passively into cells and is retained only in hypoxic areas after a 2-electron reduction reaction (13). It is well established that hypoxia is associated with aggressive tumor phenotype and with pronounced chemoresistance dependent on the higher expression and stabilization of the heterodimeric hypoxia-inducible factor complex and on the overexpression of direct targets such as carbonic anhydrase IX (CaIX), which is associated with worse prognosis and lower survival in several tumors (13,14). In osteosarcoma, high levels of hypoxiainducible factor 1a in tumor tissue and a high serum level of the transcription product of its target gene, vascular endothelial growth factor, are associated with a poor prognosis (15,16).…”

Biomedical Positron Emission Tomography (PET) imaging

“…Left intensity-modulated radiation therapy to the hypoxic tumour subregion, may be helpful in situations of focal as opposed to diffuse tumour hypoxia (Imam, 2010 ). Nitroimidazoles, of which the most important is 18F-fl uoromisonidazole (FMISO) (see Plate VI in the colour section between pages 182 and 183), are organic compounds that also include the antibiotic metronidazole.…”