Huizing Fokko J, Hoeben Bianca A W, Lok Jasper, Boerman Otto C, Heskamp Sandra, Bussink Johan
Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Phys Imaging Radiat Oncol. 2021 Aug 24;19:145-150. doi: 10.1016/j.phro.2021.08.004. eCollection 2021 Jul.
Tumor 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 [In]-girentuximab-F(ab') to image Carbonic Anhydrase IX (CAIX), an enzyme upregulated under hypoxic conditions.
Athymic 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% O). Next, [In]-girentuximab-F(ab') was injected and 24 h later mice were euthanized for 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.
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. 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 [In]-girentuximab-F(ab') did not discriminate atovaquone-treated versus control tumors.
Atovaquone decreased CAIX expression only in the FaDu tumor model. [In]-girentuximab-F(ab') 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.
肿瘤缺氧是放射抵抗的重要原因，且与不良预后相关。单光子发射计算机断层扫描（SPECT）成像能够显示肿瘤特征。我们研究了SPECT放射性示踪剂[铟]-吉妥昔单抗-F(ab')，用于对碳酸酐酶IX（CAIX）进行成像，CAIX是一种在缺氧条件下上调的酶。
对皮下接种了FaDu或SCCNij202头颈部鳞状细胞癌（HNSCC）异种移植瘤的无胸腺小鼠，用阿托伐醌治疗或置于缺氧舱（8%氧气）中。接下来，注射[铟]-吉妥昔单抗-F(ab')，24小时后对小鼠实施安乐死以进行生物分布、肿瘤放射自显影及肿瘤免疫组化染色。对肿瘤切片进行缺氧、CAIX表达、血管及灌注分析。此外，在FaDu模型中确定了阿托伐醌对微型SPECT扫描的影响。
与FaDu中的对照肿瘤相比，阿托伐醌使CAIX表达降低了69%（p = 0.017），而在SCCNij202肿瘤中未观察到差异。缺氧呼吸在两种肿瘤模型中均未增加CAIX表达或缺氧染色，但确实影响了坏死肿瘤部分。尽管CAIX表达存在差异，但阿托伐醌治疗组的示踪剂摄取与对照组相比无显著差异。此外，用[铟]-吉妥昔单抗-F(ab')进行的SPECT成像无法区分阿托伐醌治疗组与对照组肿瘤。
阿托伐醌仅在FaDu肿瘤模型中降低了CAIX表达。[铟]-吉妥昔单抗-F(ab')特异性靶向HNSCC异种移植瘤中表达CAIX的区域，但血管密度和坏死的差异很可能影响了示踪剂在肿瘤中的摄取，因此使CAIX表达变化的定量变得复杂。
