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. 2024 Mar-Apr;38(2):574-586.
doi: 10.21873/invivo.13476.

Concomitant [18F]F-FAZA and [18F]F-FDG Imaging of Gynecological Cancer Xenografts: Insight into Tumor Hypoxia

Zita Kepes  1 , Eva Hegedus  2 , Tamas Sass  3 , Csaba Csikos  2   4 , Judit P Szabo  2 , Viktoria Szugyiczki  5 , István Hajdu  2 , Istvan Kertesz  2 , Gabor Opposits  2 , Jozsef Imrek  6 , Laszlo Balkay  2 , Ferenc Krisztián Kalman  7 , Gyorgy Trencsenyi  2
Affiliations

Concomitant [18F]F-FAZA and [18F]F-FDG Imaging of Gynecological Cancer Xenografts: Insight into Tumor Hypoxia

Zita Kepes et al. In Vivo. 2024 Mar-Apr.

Abstract

Background/aim: Herein we assessed the feasibility of imaging protocols using both hypoxia-specific [18F]F-FAZA and [18F]F-FDG in bypassing the limitations derived from the non-specific findings of [18F]F-FDG PET imaging of tumor-related hypoxia.

Materials and methods: CoCl2-generated hypoxia was induced in multidrug resistant (Pgp+) or sensitive (Pgp-) human ovarian (Pgp- A2780, Pgp+ A2780AD), and cervix carcinoma (Pgp- KB-3-1, Pgp+ KB-V-1) cell lines to establish corresponding tumor-bearing mouse models. Prior to [18F]F-FDG/[18F]F-FAZA-based MiniPET imaging, in vitro [18F]F-FDG uptake measurements and western blotting were used to verify the presence of hypoxia.

Results: Elevated GLUT-1, and hexokinase enzyme-II expression driven by CoCl2-induced activation of hypoxia-inducible factor-1α explains enhanced cellular [18F]F-FDG accumulation. No difference was observed in the [18F]F-FAZA accretion of Pgp+ and Pgp- tumors. Tumor-to-muscle ratios for [18F]F-FAZA measured at 110-120 min postinjection (6.2±0.1) provided the best contrasted images for the delineation of PET-oxic and PET-hypoxic intratumor regions. Although all tumors exhibited heterogenous uptake of both radiopharmaceuticals, greater differences for [18F]F-FAZA between the tracer avid and non-accumulating regions indicate its superiority over [18F]F-FDG. Spatial correlation between [18F]F-FGD and [18F]F-FAZA scans confirms that hypoxia mostly occurs in regions with highly active glucose metabolism.

Conclusion: The addition of [18F]F-FAZA PET to [18F]F-FGD imaging may add clinical value in determining hypoxic sub-regions.

Keywords: Cervix xenotransplants; GLUT-1 transporter; [18F]F-FAZA; [18F]F-FDG; hexokinase enzyme-II; hypoxia; hypoxia-inducible factor-1α (HIF-1α); ovarian xenotransplants; positron emission tomography (PET); preclinical.

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Conflict of interest statement

The Authors declare no conflicts of interest in relation to this study.

Figures

Figure 1
Figure 1. [18F]F-FDG uptake by KB-3-1 and A2780 cells. [18F]-Fluorodeoxyglucose; [18F]: Fluorine-18 ([18F]F-FDG) accumulation in KB-3-1 cells incubated with CoCl2 for 24 and 48 hs, and the radioactivity in control KB-3-1 cells (Panel A). The [18F]F-FDG uptake by KB-3-1 cells incubated for 24 h was significantly higher at all investigated time points compared both to the untreated control cells and to cells that were incubated for 48 h. The [18F]F-FDG uptake by A2780 cells administered with CoCl2 for 24 and 48 h and the radioactivity in the control A2780 cells (Panel B). The radioactivity in A2780 cells treated for 24 h was remarkably higher at the 30- and 60-min time points in comparison with the naïve control cells as well as cells administered with CoCl2 for 48 h. At the 15 min time point, the [18F]F-FDG accretion in the A2780 cells incubated for 24 h was considerably higher than the radioactivity in the untreated cells. *p≤0.05; **p≤0.01.
Figure 2
Figure 2. Western blot analyses of CoCl2-treated KB-3-1 and A2780 cells and their control counterparts. Expression levels of HIF-1α, HKII enzyme, and GLUT-1 transporter in CoCl2-incubated KB-3-1 (Panel A), and A2780 (Panel B) cells as well as in control KB-3-1 (Panel A) and A2780 (Panel B) cells.
Figure 3
Figure 3. Quantitative assessment of the [18F]F-fluoroazomycin arabinoside ([18F]F-FAZA) uptake by the investigated Pgp+ and Pgptumor xenografts. The standardized uptake value (SUV) (mean and max) values and the tumor-to-muscle (T/M) ratios (mean and max) of permeability glycoprotein (Pgp)- A2780 and KB-3-1 and Pgp+ A2780AD and KB-V-1 tumor xenografts for [18F]F-FAZA are demonstrated.
Figure 4
Figure 4. Temporal kinetics of Fluorine-18 F-fluoroazomycin arabinoside ([18F]F-FAZA) accumulation. The real-time temporal accumulation kinetics of the hypoxic tumor regions and the background (muscle) for [18F]F-FAZA are shown. SUV: Standardized uptake value.
Figure 5
Figure 5. Temporal kinetics of the Fluorine-18 fluoroazomycin arabinoside ([18F]F-FAZA) accumulation in the hypoxic and non-hypoxic regions of the investigated tumors. [18F]F-FAZA accumulation in a representative tumor xenograft (KB-3-1) at 20 min intervals from the start of the radiotracer injection (0 min) until the end point (140 min) of the dynamic acquisition (Panel A and C). Temporal uptake kinetics of [18F]F-FAZA in the hypoxic (red line) and non-hypoxic (black line) regions of the investigated tumors (Panel B). SUV: Standardized uptake value.
Figure 6
Figure 6. [18F]F-FDG and [18F]F-FAZA MiniPET examinations of SCID mice xenotransplanted with A2780, A2780AD, KB-3-1, and KBV-1 tumor cell lines. Representative coronal [18F]F-FDG and [18F]FFAZA positron emission tomography images of severe combined immunodeficient mice xenotransplanted with A2780, A2780AD, KB-3-1, and KB-V-1 tumor cell lines. Black arrows: Pgp negative tumors; red arrows: Pgp positive tumors. [18F]: Fluorine-18; [18F]F-FDG: [18F]Fluoro-2-deoxy-D-glucose; [18F]F-FAZA: [18F]F-fluoroazomycin arabinoside; SUV: standardized uptake value.
Figure 7
Figure 7. Quantitative evaluation of intratumor [18F]F-FDG and [18F]F-FAZA radiotracer uptake. Average SUVmean values of the intratumor areas with (+) or without (-) [18F]F-FDG/[18F]F-FAZA accumulation. **p≤0.01. [18F]: Fluorine-18; [18F]F-FDG: [18F]Fluoro-2-deoxy-D-glucose; [18F]F-FAZA: [18F]F-fluoroazomycin arabinoside; SUV: standardized uptake value.
Figure 8
Figure 8. Representative [18F]F-FDG and [18F]F-FAZA PET images of the hypoxic tumor regions. [18F]F-FDG and [18F]F-FAZA uptake patterns in the hypoxic tumor regions. The red arrows indicate the overlaps between the uptakes of the two radiopharmaceuticals. [18F]: Fluorine-18; [18F]F-FDG: [18F]Fluoro-2-deoxy-D-glucose; [18F]FFAZA: [18F]F-fluoroazomycin arabinoside; PET: positron emission tomography; SUV: standardized uptake value.
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