Summary In experimental mouse tumors, high-dose irradiation in a single fraction caused progressive increase in tumor cell death in 2 to 5 days. Such delayed tumor cell deaths appeared to be due to radiation-induced deterioration of intratumor microenvironment characterized by profound reduction of blood perfusion and increase in hypoxia. Similar secondary and indirect cell death may play an important role in clinical stereotactic body radiation therapy and stereotactic radiation surgery. Purpose The purpose of this study was to reveal the biological mechanisms underlying stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS). Methods and Materials 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.

Mixtures of OXONE ® and hydrobromic acid or hydrochloric acid afford solutions of bromine or chlorine, respectively. aBromo-or a-chloro-a,b-unsaturated carbonyl compounds were prepared by addition of hydrobromic acid or hydrochloric acid to the mixture of a,b-unsaturated carbonyl compounds and OXONE ® in CH 2 Cl 2 followed by treatment of Et 3 N in moderate to good yields.

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