Focus on the Controversial Aspects of (64)Cu-ATSM in Tumoral Hypoxia Mapping by PET Imaging - PubMed (original) (raw)

Review

Focus on the Controversial Aspects of (64)Cu-ATSM in Tumoral Hypoxia Mapping by PET Imaging

Mathilde Colombié et al. Front Med (Lausanne). 2015.

Abstract

Mapping tumor hypoxia is a great challenge in positron emission tomography (PET) imaging as the precise functional information of the biological processes is needed for many effective therapeutic strategies. Tumor hypoxia has been widely reported as a poor prognostic indicator and is often associated with tumor aggressiveness, chemo- and radio-resistance. An accurate diagnosis of hypoxia is a challenge and is crucial for providing accurate treatment for patients' survival benefits. This challenge has led to the emergence of new and novel PET tracers for the functional and metabolic characterization of tumor hypoxia non-invasively. Among these tracers, copper semicarbazone compound [64Cu]-diacetyl-bis(N (4)-methylthiosemicarbazone) (=64Cu-ATSM) has been developed as a tracer for hypoxia imaging. This review focuses on 64Cu-ATSM PET imaging and the concept is presented in two sections. The first section describes its in vitro development and pre-clinical testing and particularly its affinity in different cell lines. The second section describes the controversial reports on its specificity for hypoxia imaging. The review concludes that 64Cu-ATSM - more than a hypoxic tracer, exhibits tracer accumulation in tumor, which is linked to the redox potential and reactive oxygen species. The authors concluded that 64Cu-ATSNM is a marker of over-reduced cell state and thus an indirect marker for hypoxia imaging. The affinity of 64Cu-ATSM for over-reduced cells was observed to be a complex phenomenon. And to provide a definitive and convincing mechanism, more in vivo studies are needed to prove the diagnostic utility of 64Cu-ATSM.

Keywords: [64Cu]-ATSM; cancer; hypoxia; positron emission tomography; radiopharmaceutical; reactive oxygen species.

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Figures

Figure 1

Figure 1

[64Cu]-diacetyl-bis(_N_4-methylthiosemicarbazone) (_=_64Cu-ATSM).

Figure 2

Figure 2

Overview of the cellular 64Cu-ATSM uptake and retention mechanisms. In hypoxic condition, the Cu(II)-ATSM (oxidation level of copper-64 is +II) is reduced to Cu(I)-ATSM (oxidation level of copper-64 is +I) then the complex became instable and free copper-64 is trapped and accumulate in intracellular copper chaperones proteins.

Figure 3

Figure 3

Overproduction of reductive species (NADPH and NADH) in mitochondria during hypoxia. Under normoxia, NADH produced during the tricarboxylic acid (TCA) cycle are reduced in NAD+ and the respiratory chain drove the electron (dash arrow) to dioxygen with a proton flux on the intermembrane space whose flow back on the mitochondrial matrix by the ATP synthase produced ATP. During hypoxia, the respiratory chain is inhibited and we observe an accumulation of overreduced species (NADH and NADPH) and a diminution (in long-term) of ROS production.

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