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Int J Radiat Oncol Biol Phys. 2016 Jul 1;95(3):1022-1031. doi: 10.1016/j.ijrobp.2016.01.064. Epub 2016 Feb 13.

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.

Author information

1
Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.
2
Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea.
3
Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
4
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.
5
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.
6
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.
7
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut.
8
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.
9
Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea. Electronic address: goneahn@postech.ac.kr.

Abstract

PURPOSE:

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.

METHODS AND MATERIALS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

PMID:
27130790
DOI:
10.1016/j.ijrobp.2016.01.064
[Indexed for MEDLINE]

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