克服肥胖小鼠中分次放疗疗效降低的问题

Purpose/Objective(s): Obesity is a medical condition of excess adiposity characterized by chronic inflammation and connected to comorbidities including metabolic disorders and cancer. Identifying how to best treat the growing number of obese cancer patients is paramount particularly as clinical data has implicated poorer outcomes following radiotherapy (RT) in obese patients. We observed using preclinical diet induced obesity (DIO) models that obesity promotes resistance to local fractionated RT; the aims of the current study were to identify the drivers mediating this resistance and if through altered dosing strategies it may be overcome. Materials/Methods: In vivo obesity models consisted of C57BL/6 diet induced obese (DIO) alongside age matched controls. A syngeneic tumor model(3LL) was utilized for these studies in combination with local RT administered to anesthetized mice (per IACUC guidelines). RT was performed on a 5cm water block with tumors centered in a 2 cm electron light field cutout using a 5mm bolus and treated using 6MeV electron at the desired dose (3x 4Gy fractions or 1x12Gy). In collection studies tumor tissues were harvested either immediately after irradiation or at least a week following treatment regimen for additional analysis including immunofluorescence, RNA, and protein analysis. Results : We observed that DIO mice demonstrated resistance to a fractionated local RT regimen (4Gy x 3) with no significant change in tumor burden while lean mice had significantly decreased compared to untreated controls. To evaluate if obesity associated resistance could be overcome in DIO mice, we administered a single ablative dose of 12Gy. We observed that a single dose of 12Gy was effective in both DIO and lean mice with a comparable significant decrease in tumor burden. Notably, DIO mice only responded to ablative RT doses while lean mice responded to both fractionated and ablative RT doses. Analysis of yH2AX immunofluorescence staining of treated and untreated tumors demonstrated that DIO mice had increased DNA damage and repair at baseline and following treatment. RNA sequencing of tumors confirmed increases in oxidative stress and DNA repair mechanisms Conclusion: We identified that DIO mice are resistant to fractionated RT demonstrating reduced treatment efficacy when compared to lean counterparts. However, using a single ablative dose DIO mice demonstrated significant reductions in tumor burden. The observation that tumors from DIO mice had greater baseline levels of yH2AX illustrates increased DNA repair mechanisms, likely secondary to increased baseline oxidative stress in the obese setting, which we hypothesize is diminishing lower dose fractionated RT efficacy. These data have direct implications for patient care as understanding how obesity impacts RT response may assist in developing strategies to overcome RT resistance and improve outcomes in patients with obesity.