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The British Journal of Radiology Jan 2019The concept of tumour hypoxia as a cause of radiation resistance has been prevalent for over 100 years. During this time, our understanding of tumour hypoxia has matured... (Review)
Review
The concept of tumour hypoxia as a cause of radiation resistance has been prevalent for over 100 years. During this time, our understanding of tumour hypoxia has matured with the recognition that oxygen tension within a tumour is influenced by both diffusion and perfusion mechanisms. In parallel, clinical strategies to modify tumour hypoxia with the expectation that this will improve response to radiation have been developed and tested in clinical trials. Despite many disappointments, meta-analysis of the data on hypoxia modification confirms a significant impact on both tumour control and survival. Early trials evaluated hyperbaric oxygen followed by a generation of studies testing oxygen mimetics such as misonidazole, pimonidazole and etanidazole. One highly significant result stands out from the use of nimorazole in advanced laryngeal cancer with a significant advantage seen for locoregional control using this radiosensitiser. More recent studies have evaluated carbogen and nicotinamide targeting both diffusion related and perfusion related hypoxia. A significant survival advantage is seen in muscle invasive bladder cancer and also for locoregional control in hypopharygeal cancer associated with a low haemoglobin. New developments include the recognition that mitochondrial complex inhibitors reducing tumour oxygen consumption are potential radiosensitising agents and atovaquone is currently in clinical trials. One shortcoming of past hypoxia modifying trials is the failure to identify oxygenation status and select those patient with significant hypoxia. A range of biomarkers are now available including histological necrosis, immunohistochemical intrinsic markers such as CAIX and Glut 1 and hypoxia gene signatures which have been shown to predict outcome and will inform the next generation of hypoxia modifying clinical trials.
Topics: Animals; Cell Hypoxia; Female; Humans; Male; Misonidazole; Neoplasms; Niacinamide; Oxygen Consumption; Radiation-Sensitizing Agents; Randomized Controlled Trials as Topic; Risk Assessment; Survival Analysis; Treatment Outcome; Tumor Hypoxia
PubMed: 29979089
DOI: 10.1259/bjr.20170966 -
British Medical Journal Oct 1980
Topics: Humans; Hyperbaric Oxygenation; Misonidazole; Neoplasms; Nervous System Diseases; Radiation-Sensitizing Agents
PubMed: 7427595
DOI: No ID Found -
Current Radiopharmaceuticals 2020FDG PET/CT imaging has an established role in lung cancer (LC) management. Whilst it is a sensitive technique, FDG PET/CT has a limited specificity in the... (Review)
Review
BACKGROUND
FDG PET/CT imaging has an established role in lung cancer (LC) management. Whilst it is a sensitive technique, FDG PET/CT has a limited specificity in the differentiation between LC and benign conditions and is not capable of defining LC heterogeneity since FDG uptake varies between histotypes.
OBJECTIVE
To get an overview of new radiopharmaceuticals for the study of cancer biology features beyond glucose metabolism in LC.
METHODS
A comprehensive literature review of PubMed/Medline was performed using a combination of the following keywords: "positron emission tomography", "lung neoplasms", "non-FDG", "radiopharmaceuticals", "tracers".
RESULTS
Evidences suggest that proliferation markers, such as 18F-Fluorothymidine and 11CMethionine, improve LC staging and are useful in evaluating treatment response and progression free survival. 68Ga-DOTA-peptides are already routinely used in pulmonary neuroendocrine neoplasms (NENs) management and should be firstly performed in suspected NENs. 18F-Fluoromisonidazole and other radiopharmaceuticals show a promising impact on staging, prognosis assessment and therapy response in LC patients, by visualizing hypoxia and perfusion. Radiolabeled RGD-peptides, targeting angiogenesis, may have a role in LC staging, treatment outcome and therapy. PET radiopharmaceuticals tracing a specific oncogene/signal pathway, such as EGFR or ALK, are gaining interest especially for therapeutic implications. Other PET tracers, like 68Ga-PSMA-peptides or radiolabeled FAPIs, need more development in LC, though, they are promising for therapy purposes.
CONCLUSION
To date, the employment of most of the described tracers is limited to the experimental field, however, research development may offer innovative opportunities to improve LC staging, characterization, stratification and response assessment in an era of increased personalized therapy.
Topics: Acetates; Carbon Radioisotopes; Dideoxynucleosides; Fluorodeoxyglucose F18; Gallium Isotopes; Gallium Radioisotopes; Humans; Lung Neoplasms; Methionine; Misonidazole; Neoplasm Staging; Neuroendocrine Tumors; Peptides; Peptides, Cyclic; Positron Emission Tomography Computed Tomography; Quinolines; Radiopharmaceuticals; Sensitivity and Specificity
PubMed: 31868150
DOI: 10.2174/1874471013666191223151402 -
The British Journal of Radiology Jan 2019Nitroimidazoles have been extensively explored as hypoxic cell radiosensitizers but have had limited clinical success, with efficacy restricted by toxicity. However,... (Review)
Review
Nitroimidazoles have been extensively explored as hypoxic cell radiosensitizers but have had limited clinical success, with efficacy restricted by toxicity. However, they have proven clinically useful as probes for tumour hypoxia. Both applications, and probably much of the dose-limiting toxicities, reflect the dominant chemical property of electron affinity or ease of reduction, associated with the nitro substituent in an aromatic structure. This single dominant property affords unusual, indeed extraordinary flexibility in drug or probe design, suggesting further development is possible in spite of earlier limitations, in particular building on the benefit of hindsight and an appreciation of errors made in earlier studies. The most notable errors were: the delay in viewing cellular thiol depletion as a likely common artefact in testingĀ ; slow recognition of pH-driven concentration gradients when compounds were weak acids and bases; and a failure to explore the possible involvement of pH and ascorbate in influencing hypoxia probe binding. The experience points to the need to involve a wider range of expertise than that historically involved in many laboratories when studying the effects of chemicals on radiation response or using diagnostic probes.
Topics: Animals; Cell Hypoxia; Cell Survival; Dose-Response Relationship, Drug; Humans; Misonidazole; Oxygen Consumption; Radiation-Sensitizing Agents; Sensitivity and Specificity; Tumor Hypoxia
PubMed: 29303355
DOI: 10.1259/bjr.20170915 -
The British Journal of Radiology Dec 2011Hypoxia plays a central role in tumour development, angiogenesis, growth and resistance to treatment. Owing to constant developments in medical imaging technology,... (Review)
Review
Hypoxia plays a central role in tumour development, angiogenesis, growth and resistance to treatment. Owing to constant developments in medical imaging technology, significant advances have been made towards in vitro and in vivo imaging of hypoxia in a variety of tumours, including gliomas of the central nervous system. The aim of this article is to review the literature on imaging approaches currently available for measuring hypoxia in human gliomas and provide an insight into recent advances and future directions in this field. After a brief overview of hypoxia and its importance in gliomas, several methods of measuring hypoxia will be presented. These range from invasive monitoring by Eppendorf polarographic O(2) microelectrodes, positron electron tomography (PET) tracers based on 2-nitroimidazole compounds [(18)F-labelled fluoro-misonidazole ((18)F-MISO) or 1-(2-[((18))F]fluoro-1-[hydroxymethyl]ethoxy)methyl-2-nitroimidazole (FRP-170)], (64)Cu-ATSM Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) or (99m)Tc- and (68)Ga-labelled metronidazole (MN) agents to advanced MRI methods, such as blood oxygenation level dependent (BOLD) MRI, oxygen-enhanced MRI, diffusion-weighted MRI (DWI-MRI), dynamic contrast-enhanced MRI (DCE-MRI) and (1)H-magnetic resonance spectroscopy.
Topics: Animals; Brain Neoplasms; Contrast Media; Glioma; Humans; Hypoxia; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Positron-Emission Tomography; Radiopharmaceuticals
PubMed: 22433825
DOI: 10.1259/bjr/82292521 -
British Journal of Cancer Apr 2017Pathological angiogenesis involves complex and dynamic interactions between tumour cells and other lineages existing in the microenvironment of the tumour. Preclinical... (Review)
Review
Pathological angiogenesis involves complex and dynamic interactions between tumour cells and other lineages existing in the microenvironment of the tumour. Preclinical and clinical data suggest that tumours can show dual, different adaptive responses against antiangiogenic agents: one successful adaptation is vascular normalisation, whereas the second adaptation is elicited through vascular trimming and increased hypoxia. These phenomena depend on the type of tumour and the type of agent. The classical approach for investigating acquired resistance against antiangiogenic agents is to identify compensatory signalling pathways emerging in response to VEGF blockade, which has led to the development of highly effective drugs; however, ultimately these drugs fail. Here we review how the dual stromal adaptive patterns determine the mechanisms of escape that go beyond the reprogramming of signal transduction pathways, which obliges us to investigate the tumour as an ecosystem and to develop uni- and multicompartmental models that explain drug resistance involving metabolic and immune reprogramming. We also propose a method for facilitating personalised therapeutic decisions, which uses 18F-fluoromisonidazole-positron emission tomography to monitor the dual stromal response in tumours of individual patients.
Topics: Angiogenesis Inhibitors; Cell Hypoxia; Drug Resistance, Neoplasm; Humans; Misonidazole; Neovascularization, Pathologic; Precision Medicine; Stromal Cells; Tumor Microenvironment; Vascular Endothelial Growth Factor A
PubMed: 28301873
DOI: 10.1038/bjc.2017.69 -
Biochemical Pharmacology Jan 1986Misonidazole is a metabolically active drug. Its addition to cells causes an immediate alteration in cellular electron transfer pathways. Under aerobic conditions the... (Review)
Review
Misonidazole is a metabolically active drug. Its addition to cells causes an immediate alteration in cellular electron transfer pathways. Under aerobic conditions the metabolic alterations can result in futile cycling with electron transfer to oxygen and production of peroxide. Thiol levels are extremely important in protecting the cell against the peroxide formation and potentially hazardous conditions for hydroxyl radical production. Nevertheless such electron shunting out of cellular metabolism will result in alterations in pentose cycle, glycolysis and cellular capacity to reduce metabolites to essential intermediates needed in DNA metabolism (i.e. deoxyribonucleotides). Glutathione must be depleted to very low levels before toxic effects of misonidazole and other nitro compounds are manifested in cell death via peroxidative damage. Under hypoxic conditions misonidazole also diverts the pentose cycle via its own reduction; however, unlike the aerobic conditions, there are a number of reductive intermediates produced that react with non-protein thiols such as GSH as well as protein thiols. The reaction with protein thiols results in the inhibition of glycolysis and other as yet undetermined enzyme systems. The consequences of the hypoxic pretreatment of cells with nitro compounds are increased vulnerability to radiation and chemotherapeutic drugs such as L-PAM, cis-platinum and bleomycin. The role that altered enzyme activity has in the cellular response to misonidazole and chemotherapeutic agents remains to be determined. It is also clear that the GSH depleted state not only makes cells more vulnerable to oxidative stress but also to hypoxic intermediates produced by the reduction of misonidazole beyond the one electron stage. The relevancy of the present work to the proposed use of thiol depletion in vivo to enhance the radiation or chemotherapeutic response of tumor tissue lies with the following considerations. Apparently, spontaneous peroxidative damage to normal tissue such as liver can occur with GSH depletion to 10-20% of control and with other normal tissue when GSH reaches 50% of control. This situation can obviously become more critical if peroxide producing drugs are administered. The only advantage to such combined drug treatments would lie in the possibility that tumors vary in their catalase and peroxidase activity and consequently may be more vulnerable to oxidative stress (cf. review by Meister. Our tumor model, the A549 human lung carcinoma cell in vitro, appears to be an exception because it has catalase, peroxidase and a high content of GSH.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Animals; Buthionine Sulfoximine; Catalase; Cell Division; Cell Survival; Etanidazole; Free Radicals; Glucose; Glutathione; Glycolysis; Hexosephosphates; Humans; Hypoxia; Methionine Sulfoximine; Microbodies; Microsomes; Misonidazole; Mitochondria; Nitroimidazoles; Oxidation-Reduction; Pentoses; Peroxidases; Sulfhydryl Compounds
PubMed: 2934068
DOI: 10.1016/0006-2952(86)90561-7 -
The British Journal of Radiology Aug 2017Oxygen distribution is a major determinant of treatment success in radiotherapy, with well-oxygenated tumour regions responding by up to a factor of three relative to... (Review)
Review
Oxygen distribution is a major determinant of treatment success in radiotherapy, with well-oxygenated tumour regions responding by up to a factor of three relative to anoxic volumes. Conversely, tumour hypoxia is associated with treatment resistance and negative prognosis. Tumour oxygenation is highly heterogeneous and difficult to measure directly. The recent advent of functional hypoxia imaging modalities such as fluorine-18 fluoromisonidazole positron emission tomography have shown promise in non-invasively determining regions of low oxygen tension. This raises the prospect of selectively increasing dose to hypoxic subvolumes, a concept known as dose painting. Yet while this is a promising approach, oxygen-mediated radioresistance is inherently a multiscale problem, and there are still a number of substantial challenges that must be overcome if hypoxia dose painting is to be successfully implemented. Current imaging modalities are limited by the physics of such systems to have resolutions in the millimetre regime, whereas oxygen distribution varies over a micron scale, and treatment delivery is typically modulated on a centimetre scale. In this review, we examine the mechanistic basis and implications of the radiobiological oxygen effect, the factors influencing microscopic heterogeneity in tumour oxygenation and the consequent challenges in the interpretation of clinical hypoxia imaging (in particular fluorine-18 fluoromisonidazole positron emission tomography). We also discuss dose-painting approaches and outline challenges that must be addressed to improve this treatment paradigm.
Topics: Cell Hypoxia; Humans; Hypoxia; Misonidazole; Neoplasms; Positron-Emission Tomography; Radiation-Sensitizing Agents; Radiotherapy Dosage
PubMed: 28540739
DOI: 10.1259/bjr.20160939