Key Points
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Detection of the early responses of tumours to treatment could be used to guide subsequent therapy, allowing rapid selection of the most appropriate therapy, with attendant welfare benefits for the patient and cost benefits for the health-care system.
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Tumour responses to treatment are conventionally assessed by imaging measurements of tumour size. However, tumour shrinkage can take weeks or even months to become apparent or, with some therapies, might not occur at all, despite a positive response to treatment.
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Imaging measurements of tumour biochemistry or cell biology can give an earlier indication of whether a tumour is responding to treatment than measurements of tumour size. For example, measurements of the reduction in tumour uptake of a radiolabelled glucose analogue, 2-[18F]fluoro-2-deoxy-D-glucose, are already used clinically to detect tumour responses to treatment, often before there is any change in tumour size.
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The radionuclide imaging techniques, positron-emission tomography and single photon-emission computed tomography, can be used to monitor receptor expression using appropriately labelled receptor ligands. As these techniques are so sensitive (they can detect concentrations in the 10−12–10−10 M range), the agents can be administered at sub-pharmacological doses.
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Labelling of cell metabolites (for example, amino acids, acetate, the glucose analogue fluorodeoxyglucose) with positron-emitting isotopes (11C and 18F) allows imaging of tumour metabolism in the clinic.
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Magnetic resonance imaging of the protons in tissue water gives relatively high-resolution images of tissue morphology. By using receptor ligands that have been labelled with paramagnetic tags that affect the spin relaxation times, magnetic resonance imaging measurements of tissue water can be used to image receptor expression indirectly.
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Magnetic resonance spectroscopy (MRS) can be used to detect tumour metabolites in vivo. Phosphorus-31 MRS can be used to monitor the levels of ATP, inorganic phosphate and intracellular pH and 1H MRS the levels of various abundant metabolites, including lactate, neutral lipids and phospholipid metabolites, such as phosphocholine.
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Nuclear spin hyperpolarization can be used to dramatically enhance the sensitivity
(> 10,000×) of the magnetic resonance experiment. Hyperpolarization of injected molecules allows spectroscopic imaging of their distribution in the body and subsequent metabolism.
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The availability of these clinical imaging modalities in configurations that can be used with animal models of disease in the laboratory should promote the translation of new imaging techniques from the laboratory into the clinic.
Abstract
Tumour responses to treatment are still largely assessed from imaging measurements of reductions in tumour size. However, this can take several weeks to become manifest and in some cases may not occur at all, despite a positive response to treatment. There has been considerable interest, therefore, in non-invasive techniques for imaging tissue function that can give early evidence of response. These can be used in clinical trials of new drugs to give an early indication of drug efficacy, and subsequently in the clinic to select the most effective therapy at an early stage of treatment.
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Kevin Brindle has a research agreement with GE Healthcare that funds work on imaging of hyperpolarized cell metabolites.
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DATABASES
National Cancer Institute Drug Dictionary
FURTHER INFORMATION
Glossary
- Isotropic image resolutions
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Image resolution in the three orthogonal image axes.
- Voxel volume
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The volume of the volume elements of the image. For example, an image with a resolution of 0.1 × 0.1 × 1.0 mm would have a voxel volume of 10 nl.
- Cyclotron
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A particle accelerator. Collision of a particle (for example, a proton or deuteron) with a target can be used to produce a short-lived positron-emitting isotope.
- Spin relaxation times
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Loss of net magnetization in the x–y plane is described by a time constant (T2) called the spin–spin relaxation time. Return of net magnetization to the z axis is described by the spin-lattice relaxation time (T1). Thus T1 ≥ T2. For water protons in a biological system T1 is usually of the order of seconds and T2 tens of milliseconds.
- L-type amino-acid transporter system
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The L-type amino-acid transporter is a Na+-independent neutral amino-acid transporter that has a broad substrate selectivity and has been shown to be upregulated in some cancers.
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Brindle, K. New approaches for imaging tumour responses to treatment. Nat Rev Cancer 8, 94–107 (2008). https://doi.org/10.1038/nrc2289
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DOI: https://doi.org/10.1038/nrc2289