Results of the First Randomized Controlled Trial of Deep Brain Stimulation in Treatment-Resistant Depression.

induced phenotype in combination with the prodrug, there was a significant increase in cell death, with up to 80% of cells dead after 48 hours. Lee et al then performed real-time tracking of prodrug activation in cancer cell cultures. Twenty-four hours after treatment with radiation and prodrug, more than half of the doxorubicin had been activated and localized to the nucleus. Without radiation, the prodrug remained in the cytoplasm of the cells. Administration of a caspase inhibitor prevented this translocation of doxorubicin and prevented cell death. The real beauty of RIATC is its use of a targeted inducer of the apoptotic phenotype, SRS, rather than diffuse radiation therapy. One of the many benefits of SRS is that it can provide an apoptosis-inducing radiation dose in a precise, accurate, and selective fashion and limit injury to surrounding tissues. Mice harboring a cancerous tumor in the body had their tumors treated with the Gamma Knife while also receiving the prodrug intravenously. This combination was significantly more effective at controlling tumor growth compared with SRS or prodrug alone. Moreover, the RIATC-treated mice demonstrated none of the systemic toxicity seen with the administration of an equivalent dose of doxorubicin. A real-time fluorescence assay of apoptosis via caspase-3 activity in the mouse tumors demonstrated that RIATC was much more effective at inducing apoptosis compared with the prodrug alone or radiation alone (Figure). Not surprisingly, this was prevented with coadministration of a caspase-3 inhibitor. Immunohistochemical testing of the RIATC tumor tissue triggered a significant increase in caspase-3–positive cells over the control treatments (Figure). Combined, these studies establish proof of the RIATC principle. SRS has become an established treatment for brain metastases and is fast becoming the initial go-to strategy for the majority of patients. RIATC is an opportunity to create a synergy with SRS and potentially improve the already excellent tumor control rates experienced by patients with brain metastases by taking advantage of potential tumor homogenization brought about by SRS. In contrast to the use of radiation sensitizers and protectants that sensitize and protect both tumor and normal tissue, RIATC has the opportunity to synergize with the radiation administered by SRS only at the targeted sites. Its major limitation is that of most systemically administered therapies, an inability to achieve meaningful efficacy in the brain because the blood-brain barrier blocks agents out. As new systemic agents showing efficacy in the brain come online, tremendous opportunities for synergy with SRS should be explored.