The radioprotectant nano-genistein enhances radiotherapy efficacy of lung tumors in mice
Michael D. Kaytor, Artur A. Serebrenik, Karen Lapanowski, Debra McFall, Matthew C. Jones, Benjamin Movsas, Charles B. Simone, Stephen L. Brown
Abstract
Background: Radiotherapy for non-small cell lung cancer (NSCLC) can be dose-limiting due to treatment-related toxicities. Genistein has been shown to be a robust radioprotective agent in preclinical models. A novel genistein oral nanosuspension formulation (nano-genistein) has demonstrated efficacy in mitigating radiation-induced lung damage in preclinical animal models. However, while those studies have confirmed that nano-genistein can protect normal lung tissue from radiation-induced toxicities, no studies have assessed the effect of nano-genistein on lung tumors. Here, we evaluated the impact of nano-genistein on the efficacy of radiation treatment of lung tumors in a mouse xenograft model. Methods: Two separate studies were conducted utilizing human A549 cells implanted either dorsally within the upper torso or in the flank. Daily oral administration of nano-genistein (200 or 400 mg/kg/day) occurred prior to and after exposure to a single dose of thoracic or abdominal 12.5 Gy radiation. Tumor growth was monitored twice weekly, nano-genistein treatment continued for up to 20 weeks and histopathology of tissues was completed post euthanasia. Results: Continuous nano-genistein dosing was safe across all study groups in both studies. Animals receiving nano-genistein better maintained body weight following irradiation compared to corresponding vehicle treated animals. Animals that received nano-genistein also had reduced tumor growth and improved normal lung histopathology compared to those receiving vehicle suggesting that nano-genistein does not protect tumors from radiotherapy but is radioprotective of the lungs. There were no treatment-related histopathological findings noted in the skin adjacent to the tumor, esophagus, or uterus. Conclusions: These results, including the safety following extended dosing, support the continued evaluation of nano-genistein as an adjunctive treatment for patients with NSCLC undergoing radiotherapy and serve as the basis of a phase 1b/2a multicenter clinical trial.