Dataset Information

⁶⁴Cu-ATSM/⁶⁴Cu-Cl₂ and their relationship to hypoxia in glioblastoma: a preclinical study.

ABSTRACT:

Background

Diacetyl-bis(N4-methylthiosemicarbazone), labeled with 64Cu (⁶⁴Cu-ATSM) has been suggested as a promising tracer for imaging hypoxia. However, various controversial studies highlighted potential pitfalls that may disable its use as a selective hypoxic marker. They also highlighted that the results may be tumor location dependent. Here, we first analyzed uptake of Cu-ATSM and its less lipophilic counterpart Cu-Cl₂ in the tumor over time in an orthotopic glioblastoma model. An in vitro study was also conducted to investigate the hypoxia-dependent copper uptake in tumor cells. We then further performed a comprehensive ex vivo study to compare ⁶⁴Cu uptake to hypoxic markers, specific cellular reactions, and also transporter expression.

Methods

?PET was performed 14?days (¹⁸F-FMISO), 15?days (⁶⁴Cu-ATSM and ⁶⁴Cu-Cl2), and 16?days (⁶⁴Cu-ATSM and ⁶⁴Cu-Cl₂) after C6 cell inoculation. Thereafter, the brains were withdrawn for further autoradiography and immunohistochemistry. C6 cells were also grown in hypoxic workstation to analyze cellular uptake of Cu complexes in different oxygen levels.

Results

In vivo results showed that Cu-ASTM and Cu-Cl2 accumulated in hypoxic areas of the tumors. Cu-ATSM also stained, to a lesser extent, non-hypoxic regions, such as regions of astrogliosis, with high expression of copper transporters and in particular DMT-1 and CTR1, and also characterized by the expression of elevated astrogliosis. In vitro results show that 64Cu-ATSM showed an increase in the uptake only in severe hypoxia at 0.5 and 0.2% of oxygen while for ⁶⁴Cu-Cl2, the cell retention was significantly increased at 5% and 1% of oxygen with no significant rise at lower oxygen percentages.

Conclusion

In the present study, we show that Cu-complexes undoubtedly accumulate in hypoxic areas of the tumors. This uptake may be the reflection of a direct dependency to a redox metabolism and also a reflection of hypoxic-induced overexpression of transporters. We also show that Cu-ATSM also stained non-hypoxic regions such as astrogliosis.

SUBMITTER: Peres EA

PROVIDER: S-EPMC6923301 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Publications

64Cu-ATSM/64Cu-Cl2 and their relationship to hypoxia in glioblastoma: a preclinical study.

Pérès Elodie A EA Toutain Jérôme J Paty Louis-Paul LP Divoux Didier D Ibazizène Méziane M Guillouet Stéphane S Barré Louisa L Vidal Aurélien A Cherel Michel M Bourgeois Mickaël M Bernaudin Myriam M Valable Samuel S

EJNMMI research 20191219 1

<h4>Background</h4>Diacetyl-bis(N4-methylthiosemicarbazone), labeled with 64Cu (64Cu-ATSM) has been suggested as a promising tracer for imaging hypoxia. However, various controversial studies highlighted potential pitfalls that may disable its use as a selective hypoxic marker. They also highlighted that the results may be tumor location dependent. Here, we first analyzed uptake of Cu-ATSM and its less lipophilic counterpart Cu-Cl2 in the tumor over time in an orthotopic gl ...[more]

PMID: 31858290

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