title: Real-time Tumor Oxygenation Changes After Single High-dose Radiation Therapy in Orthotopic and Subcutaneous Lung Cancer in Mice: Clinical Implication for Stereotactic Ablative Radiation Therapy Schedule Optimization.
abstract: To investigate the serial changes of tumor hypoxia in response to single high-dose irradiation by various clinical and preclinical methods to propose an optimal fractionation schedule for stereotactic ablative radiation therapy.
  
  
  
  Syngeneic Lewis lung carcinomas were grown either orthotopically or subcutaneously in C57BL/6 mice and irradiated with a single dose of 15 Gy to mimic stereotactic ablative radiation therapy used in the clinic. Serial [(18)F]-misonidazole (F-MISO) positron emission tomography (PET) imaging, pimonidazole fluorescence-activated cell sorting analyses, hypoxia-responsive element-driven bioluminescence, and Hoechst 33342 perfusion were performed before irradiation (day -1), at 6 hours (day 0), and 2 (day 2) and 6 (day 6) days after irradiation for both subcutaneous and orthotopic lung tumors. For F-MISO, the tumor/brain ratio was analyzed.
  
  
  
  Hypoxic signals were too low to quantitate for orthotopic tumors using F-MISO PET or hypoxia-responsive element-driven bioluminescence imaging. In subcutaneous tumors, the maximum tumor/brain ratio was 2.87 ± 0.483 at day -1, 1.67 ± 0.116 at day 0, 2.92 ± 0.334 at day 2, and 2.13 ± 0.385 at day 6, indicating that tumor hypoxia was decreased immediately after irradiation and had returned to the pretreatment levels at day 2, followed by a slight decrease by day 6 after radiation. Pimonidazole analysis also revealed similar patterns. Using Hoechst 33342 vascular perfusion dye, CD31, and cleaved caspase 3 co-immunostaining, we found a rapid and transient vascular collapse, which might have resulted in poor intratumor perfusion of F-MISO PET tracer or pimonidazole delivered at day 0, leading to decreased hypoxic signals at day 0 by PET or pimonidazole analyses.
  
  
  
  We found tumor hypoxia levels decreased immediately after delivery of a single dose of 15 Gy and had returned to the pretreatment levels 2 days after irradiation and had decreased slightly by day 6. Our results indicate that single high-dose irradiation can produce a rapid, but reversible, vascular collapse in tumors.
authors.affiliation: Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Changhoon
authors.initials: C
authors.lastname: Song
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea.
authors.forename: Beom-Ju
authors.initials: BJ
authors.lastname: Hong
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea.
authors.forename: Seoyeon
authors.initials: S
authors.lastname: Bok
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea.
authors.forename: Chan-Ju
authors.initials: CJ
authors.lastname: Lee
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea.
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Kim
authors.affiliation: Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Sang-Rok
authors.initials: SR
authors.lastname: Jeon
authors.affiliation: Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Institute of Radiation Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Hong-Gyun
authors.initials: HG
authors.lastname: Wu
authors.affiliation: Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Yun-Sang
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Institute of Radiation Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea; Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Gi Jeong
authors.initials: GJ
authors.lastname: Cheon
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Institute of Radiation Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea; Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jin Chul
authors.initials: JC
authors.lastname: Paeng
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: David J
authors.initials: DJ
authors.lastname: Carlson
authors.affiliation: Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Institute of Radiation Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea. Electronic address: khjae@snu.ac.kr.
authors.forename: Hak Jae
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea. Electronic address: goneahn@postech.ac.kr.
authors.forename: G-One
authors.initials: GO
authors.lastname: Ahn
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000378:metabolism*; D000069473:Radiation Dose Hypofractionation; D016634:Radiosurgery / Q000379:methods*; D011879:Radiotherapy Dosage; D000072258:Tumor Hypoxia / Q000528:radiation effects*
chemical_list: D010100:Oxygen