The data in this study also indicated that pre-treatment with anti-VEGF agent 1 h prior to SDRT is required for anti-angiogenic de-repression of endothelial ASMase and consequent tumor response. This result supported our previous findings that 1 h prior to RT is the optimal time window for treating tumors using anti-angiogenic agents in combination with SDRT [14, 23]. Notably, this temporal relationship between anti-angiogenic agents and radiation differs from the tumor microvessel normalization hypothesis, which requires at least 24 h to manifest, or constraint of endothelial progenitor recruitment into the damaged site, usually delivered at 24 h prior to irradiation [18, 19]. Although the underlying mechanism remains elusive, given that SDRT increased ASMase activity and ceramide generation just within minutes, it is reasonable to assume that anti-angiogenic agents should be delivered immediately prior to irradiation to de-repress ASMase.