Tumor microenvironment-dependent ¹⁸F-FDG, ¹⁸F- Fluorothymidine, and ¹⁸F-misonidazole uptake: A pilot study in mouse models of human non-small cell lung cancer

¹⁸F-FDG, ¹⁸F-fluorothymidine, and ¹⁸F-misonidazole PET scans have emerged as important clinical tools in the management of cancer; however, none of them have demonstrated conclusive superiority. The aim of this study was to compare the intratumoral accumulation of ¹⁸F-FDG, ¹⁸F-fluorothymidine, and ¹⁸F- misonidazole and relate this to specific components of the tumor microenvironment in mouse models of human non-small cell lung cancer (NSCLC). Methods: We used NSCLC A549 and HTB177 cells to generate subcutaneous and peritoneal xenografts in nude mice. Animals were coinjected with a PET radiotracer, pimonidazole (hypoxia marker), and bromodeoxyuridine (proliferation marker) intravenously 1 h before animal euthanasia. Tumor perfusion was assessed by Hoechst 33342 injection, given 1 min before sacrifice. The intratumoral distribution of PET radiotracers was visualized by digital autoradiography and related to microscopic visualization of proliferation, hypoxia, perfusion, stroma, and necrosis. Results: NSCLC xenografts had complex structures with intermingled regions of viable cancer cells, stroma, and necrosis. Cancer cells were either well oxygenated (staining negatively for pimonidazole) and highly proliferative (staining positively for bromodeoxyuridine) or hypoxic (pimonidazole-positive) and noncycling (little bromodeoxyuridine). Hypoxic cancer cells with a low proliferation rate had high ¹⁸F-FDG and ¹⁸F-misonidazole uptake but low ¹⁸F-fluorothymidine accumulation. Well-oxygenated cancer cells with a high proliferation rate accumulated a high level of ¹⁸F- fluorothymidine but low ¹⁸F-FDG and ¹⁸F-misonidazole. Tumor stroma and necrotic zoneswere always associatedwith low ¹⁸F-FDG, ¹⁸F-misonidazole, and ¹⁸F-fluorothymidine activity. Conclusion: In NSCLC A549 and HTB177 subcutaneously or intraperitoneally growing xenografts, ¹⁸F-fluorothymidine accumulates in well-oxygenated and proliferative cancer cells, whereas ¹⁸F-misonidazole and ¹⁸F-FDG accumulate mostly in poorly proliferative and hypoxic cancer cells. ¹⁸F-FDG and ¹⁸F-misonidazole display similar intratumoral distribution patterns, and both mutually exclude ¹⁸F-fluorothymidine.