1. 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
-
Beom-Ju Hong, Seoyeon Bok, Hak Jae Kim, Yun Sang Lee, Young Eun Kim, G-One Ahn, Gi Jeong Cheon, Changhoon Song, Chan-Ju Lee, Hong-Gyun Wu, Sang-Rok Jeon, David J. Carlson, and Jin Chul Paeng
- Subjects
Male ,Cancer Research ,Lung Neoplasms ,medicine.medical_treatment ,Radiosurgery ,030218 nuclear medicine & medical imaging ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Animals ,Pimonidazole ,Bioluminescence imaging ,Radiology, Nuclear Medicine and imaging ,Lung cancer ,Radiation ,Tumor hypoxia ,business.industry ,Radiotherapy Dosage ,Tumor Oxygenation ,medicine.disease ,Mice, Inbred C57BL ,Oxygen ,Radiation therapy ,Oncology ,030220 oncology & carcinogenesis ,Tumor Hypoxia ,Radiation Dose Hypofractionation ,business ,Nuclear medicine ,Perfusion - 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.
- Published
- 2016