Indirect Tumor Cell Death After High-Dose Hypofractionated Irradiation: Implications for Stereotactic Body Radiation Therapy and Stereotactic Radiation Surgery.
OBJECTIVE
The purpose of this study was to reveal the biological mechanisms underlying stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS).


METHODS
FSaII fibrosarcomas grown subcutaneously in the hind limbs of C3H mice were irradiated with 10 to 30 Gy of X rays in a single fraction, and the clonogenic cell survival was determined with in vivo--in vitro excision assay immediately or 2 to 5 days after irradiation. The effects of radiation on the intratumor microenvironment were studied using immunohistochemical methods.


RESULTS
After cells were irradiated with 15 or 20 Gy, cell survival in FSaII tumors declined for 2 to 3 days and began to recover thereafter in some but not all tumors. After irradiation with 30 Gy, cell survival declined continuously for 5 days. Cell survival in some tumors 5 days after 20 to 30 Gy irradiation was 2 to 3 logs less than that immediately after irradiation. Irradiation with 20 Gy markedly reduced blood perfusion, upregulated HIF-1α, and increased carbonic anhydrase-9 expression, indicating that irradiation increased tumor hypoxia. In addition, expression of VEGF also increased in the tumor tissue after 20 Gy irradiation, probably due to the increase in HIF-1α activity.


CONCLUSIONS
Irradiation of FSaII tumors with 15 to 30 Gy in a single dose caused dose-dependent secondary cell death, most likely by causing vascular damage accompanied by deterioration of intratumor microenvironment. Such indirect tumor cell death may play a crucial role in the control of human tumors with SBRT and SRS.
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, Minneapolis, Minnesota; Korea Institute of Radiological and Medical Sciences, Seoul, Korea. Electronic address: songx001@umn.edu.
Chang W
CW
Song
Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
Yoon-Jin
YJ
Lee
Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Robert J
RJ
Griffin
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, Minneapolis, Minnesota.
Inhwan
I
Park
Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Nathan A
NA
Koonce
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, Minneapolis, Minnesota.
Susanta
S
Hui
Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
Mi-Sook
MS
Kim
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, Minneapolis, Minnesota.
Kathryn E
KE
Dusenbery
Minneapolis Radiation Oncology and Gamma Knife Center, University of Minnesota, Minneapolis, Minnesota.
Paul W
PW
Sperduto
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, Minneapolis, Minnesota.
L Chinsoo
LC
Cho
D000818:Animals; D002256:Carbonic Anhydrases / Q000378:metabolism; D016923:Cell Death; D015687:Cell Hypoxia; D002470:Cell Survival / Q000502:physiology / Q000528:radiation effects*; D019583:Dose Fractionation, Radiation; D005354:Fibrosarcoma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D016634:Radiosurgery / Q000379:methods*; D013997:Time Factors; D059016:Tumor Microenvironment / Q000502:physiology / Q000528:radiation effects*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D002256:Carbonic Anhydrases