Combined effect of tumor necrosis factor-related apoptosis-inducing ligandand ionizing radiation in breast cancer therapy

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent endogenous activator of the cell death pathway and functions by activating the cell surface death receptors 4 and 5 (DR4 and DR5), TRAIL is nontoxic in vivo and preferentially kills neoplastically transformed cells over norm al cells by an undefined mechanism. Radiotherapy is a common treatment for breast cancer as well as many other cancers. Here we demonstrate that ioniz ing radiation can sensitize breast carcinoma cells to TRAIL-induced apoptos is, This synergistic effect is p53-dependent and may be the result of radia tion-induced up-regulation of the TRAIL-receptor DR5, Importantly, TRAIL an d ionizing radiation have a synergistic effect in the regression of establi shed breast cancer xenografts, Changes in tumor cellularity and extracellul ar space were monitored in vivo by diffusion-weighted magnetic resonance im aging (diffusion MRI), a noninvasive technique to produce quantitative imag es of the apparent mobility of water within a tissue. Increased water mobil ity was observed in combined TRAIL- and radiation-treated tumors but not in tumors treated with TRAIL or radiation alone. Histological analysis confir med the loss of cellularity and increased numbers of apoptotic cells in TRA IL- and radiation-treated tumors. Taken together, our results provide suppo rt for combining radiation with TRAIL to improve tumor eradication and sugg est that efficacy of apoptosis-inducing cancer therapies may be monitored n oninvasively, using diffusion MRI.