Tumor Microenvironment-Dependent 18F-FDG, 18F-Fluorothymidine, and 18F-Misonidazole Uptake: A Pilot Study in Mouse Models of Human Non-Small Cell Lung Cancer

F-18-FDG, F-18-fluorothymidine, and F-18-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 F-18-FDG, F-18-fluorothymidine, and F-18-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(18)F-FDG and F-18-misonidazole uptake but low F-18-fluorothymidine accumulation. Well-oxygenated cancer cells with a high proliferation rate accumulated a high level of F-18-fluorothymidine but low F-18-FDG and F-18-misonidazole. Tumor stroma and necrotic zones were always associated with low F-18-FDG, F-18-misonidazole, and F-18-fluorothymidine activity. Conclusion: In NSCLC A549 and HTB177 subcutaneously or intraperitoneally growing xenografts, F-18-fluorothymidine accumulates in well-oxygenated and proliferative cancer cells, whereas F-18-misonidazole and F-18-FDG accumulate mostly in poorly proliferative and hypoxic cancer cells. F-18-FDG and F-18-misonidazole display similar intratumoral distribution patterns, and both mutually exclude F-18-fluorothymidine.