Abstract
Background and purposeTumor hypoxia is an important cause of radioresistance and is associated with poor outcome.SPECT (Single-photon emission computed tomography) imaging enables visualizing tumor characteristics. We investigated the SPECT-radiotracer [111In]-girentuximab-F(ab’)2 to image Carbonic Anhydrase IX (CAIX), an enzyme upregulated under hypoxic conditions.Materials and methodsAthymic mice with subcutaneous FaDu or SCCNij202 head and neck squamous cell carcinoma (HNSCC) xenografts were treated with atovaquone or were housed in a hypoxic chamber (8% O2). Next, [111In]-girentuximab-F(ab’)2 was injected and 24 h later mice were euthanized for ex vivo biodistribution, autoradiography of the tumor, and immunohistochemical staining of the tumor. Tumor sections were analyzed for hypoxia, CAIX expression, vessels, and perfusion. Also, the effect of atovaquone on microSPECT scans was determined in the FaDu model.ResultsAtovaquone decreased CAIX expression by 69% (p = 0.017) compared with control tumors in FaDu, while in the SCCNij202 tumors no difference was observed. Hypoxic breathing did not increase CAIX expression or hypoxia staining in either tumor model, but did affect the necrotic tumor fraction. Ex vivo tracer uptake in the atovaquone treated group did not differ significantly from the control group, despite the difference in CAIX expression. Furthermore, SPECT imaging with [111In]-girentuximab-F(ab’)2 did not discriminate atovaquone-treated versus control tumors.ConclusionAtovaquone decreased CAIX expression only in the FaDu tumor model. [111In]-girentuximab-F(ab’)2 specifically targets CAIX-expressing areas in HNSCC xenografts, but differences in vessel density and necrosis most likely affected tracer uptake in the tumors and therefore complicated quantification of changes in CAIX expression.
Highlights
Advanced head and neck squamous cell carcinomas (HNSCC) are treated by surgery and/or radiotherapy, often combined with con current chemotherapy
We set up experiments where we modulated the level of oxygenation towards an improved oxygenation status and a decreased oxygenation status in two different human head and neck squamous cell car cinoma (HNSCC) models. We evaluated whether this change in oxygenation status altered the Carbonic Anhydrase IX (CAIX) expression levels and tumor targeting of [111In]In-G250-F(ab’
In this study we explored the application of the tracer [111In]InG250-F(ab’)2 to assess the changes in CAIX expression induced by hypoxic gas breathing and inhibition of mitochondrial respiration with ato vaquone to reduce hypoxia in human xenografted HNSCC
Summary
Advanced head and neck squamous cell carcinomas (HNSCC) are treated by surgery and/or radiotherapy, often combined with con current chemotherapy. A prominent predictor of therapy resistance for non-surgical treat ments is tumor hypoxia. Both chemotherapy and radiotherapy are less effective in tumors with inadequate oxygenation [2,3]. Materials and methods: Athymic mice with subcutaneous FaDu or SCCNij202 head and neck squamous cell car cinoma (HNSCC) xenografts were treated with atovaquone or were housed in a hypoxic chamber (8% O2). Results: Atovaquone decreased CAIX expression by 69% (p = 0.017) compared with control tumors in FaDu, while in the SCCNij202 tumors no difference was observed. Hypoxic breathing did not increase CAIX expression or hypoxia staining in either tumor model, but did affect the necrotic tumor fraction. Conclusion: Atovaquone decreased CAIX expression only in the FaDu tumor model. [111In]-girentuximab-F(ab’) targets CAIX-expressing areas in HNSCC xenografts, but differences in vessel density and necrosis most likely affected tracer uptake in the tumors and complicated quantification of changes in CAIX expression
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