10097 Background: Recent genetic and pharmacologic mouse model studies have shown tumor microvascular endothelium is a primary target in single-dose radiotherapy, required for induction of tumor cell death. The goal of this study is to establish the human tumor microvascular response to ionizing radiation (IR), and to determine whether targeting this response with IR might improve solid tumor treatment. Methods: Fresh epithelial ovarian cancer (EOC) tissue was obtained and irradiated within 30 minutes from patients undergoing surgical resection. Tumors were sliced into 0.5cm fragments, bathed in Dulbecco’s Modification of Eagle’s Medium (DMEM) and irradiated ex vivo at 0, 7, 13, 17, 20, 25 Gy. Specimens were incubated at 37°C post-irradiation for 0, 2, 3, 4 hours, fixed in formalin and paraffin embedded. Immunohistochemistry using TUNEL-CD34 double staining was subsequently performed to detect apoptotic tumor endothelial cells. Results: 10 EOC specimens were initially studied. Tumor microvascular endothelium underwent a linear dose and time dependent apoptotic response mirroring the range reported in mouse models. Three to four hours post irradiation, 60% of endothelial cells underwent apoptosis at 17–25 Gy compared to a baseline rate of 5% in unirradiated controls. Response heterogeneity among the tumor samples was not seen. Of interest is our observation that a maximal apoptotic response obtained in glioblastoma, classically considered radioresistant, was only 30%. Conclusion: The endothelial compartment is an important target in EOC radiation response at the clinically-relevant dose range. Studies assessing endothelial cell radiosensitivity of human EOC and the impact of endothelial cell radiosensitizing agents may provide opportunities to improve radiation responsiveness of EOC. No significant financial relationships to disclose.
Ultrasound-Mediated Drug/Gene Delivery in Solid Tumor Treatment
