Modulation of Ceramide-Induced Apoptosis in Vivo

ManhattanPrj.jpg
Change in pO2 for ASMase (+/+) blue and ASMase (-/-) red.

In human subjects an unexpected effectiveness, of radiation delivered in large doses (> 15 Gy/dose) is observed. It is possible that these radiation doses stimulate a signal cascade in the host vasculature that is initiated by the acid sphingomyelinase (ASMase) gene product ceramide, which causes rapid death of microvessel endothelial cells supplying oxygen to tumor cells.  This causes a rapid onset of hypoxia, which interferes with tumor cell repair of damage induced by the radiation.  This sensitizes the tumor cells to radiation by post-radiation hypoxia.  

We compare the change in pO2 15 min. after 20 Gy radiation in ASMase knockout and wild type mice.  pO2 change is plotted in Figure; the tumor pO2change in the wild-type animal is larger than in tumors in ASMase knockout mice (p=0.02).  This is a strong argument for the proposed hypothesis.