The potential of positron-emission tomography to study anticancer-drug resistance

Abstract

Positron-emission tomography (PET) is a powerful tool for imaging and quantifying cellular and molecular processes in humans. It has enormous potential to increase our understanding of the pathophysiology of human tumours and to support the development of anticancer drugs. The ability of PET to image mechanisms of anticancer-drug resistance in vivo should be exploited in proof-of-concept studies at early stages of drug development.

Key Points

  • Positron-emission tomography (PET) is a sensitive method for imaging cellular and molecular processes in humans.

  • PET is a quantitative tool that can measure picomolar levels of drugs and ligands.

  • PET can be used to image processes involved in resistance and responses to anticancer drugs, such as pharmacokinetics and metabolism, angiogenesis, hypoxia, proliferation, apoptosis and DNA repair.

  • Spatial, temporal and functional information can be provided using PET.

  • Studies of mechanisms of resistance to the widely used anticancer agent 5-fluorouracil using PET illustrate the potential of this technique.

  • To avoid the high rate of attrition from initial drug development to regulatory approval, the ability of PET to image anticancer-drug resistance pathways should be exploited in proof-of-concept studies at an early stage of drug development.

  • Validation of new imaging probes requires multidisciplinary collaboration involving those working in PET, oncology, tumour-cell and molecular biology, and anticancer-drug discovery, and requires development within both academia and the pharmaceutical industry.

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Figure 1: 5-Fluorouracil-resistance pathways and their visualization using positron-emission tomography.
Figure 2: Positron-emission tomography visualization of drug-resistance pathways in humans, using 5-FU as an example.

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Acknowledgements

The authors thank D. R. Newell for his helpful comments on this paper.

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Correspondence to Catharine M. L West.

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The authors declare no competing financial interests.

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DATABASES

Cancer.gov

Acute myelogenous leukaemia

brain tumour

colorectal cancer

gastrointestinal cancer

gastrointestinal stromal tumour

hepatoma

melanoma

neuroblastoma

Entrez Gene

ABL

AGT

annexin V

BCR

CDKN1A

EGFR

endostatin

GLUT1

hexokinase 1

HIF-1α

KIT

PARP/PARS

P-gp

TGF-β

thymidine kinase

thymidylate synthase

Glossary

REPORTER GENE

Use of a reporter gene enables monitoring of the level of expression of a particular gene by producing a measurable product whenever the gene of interest is transcribed. The reporter gene is placed either within or near to the gene of interest under the control of a promoter that requires the presence of the product of the gene of interest to activate the expression of the reporter gene.

AREA UNDER THE CURVE (AUC)

This is the mathematical integration of the area under a curve. If the curve is for drug concentration against time it reflects drug exposure. If the curve is for a positron-emission tomography (PET) probe standardized-uptake value against time it reflects tissue exposure to the radiolabel in the PET probe (this can include the parent compound and its metabolites).

CYCLOTRON

Particle accelerator in which a magnetic field causes particles to orbit in circles and an oscillating electric field accelerates the particles. The particles collide with a target, so transforming the atoms in the target into radioactive, unstable isotopes.

MULTIDRUG-RESISTANCE PHENOTYPE

The insensitivity of various tumours to a range of chemically unrelated anticancer drugs; it is mediated by a process of inactivating the drug or removing it from the target tumour cells.

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