Response Of Breast Cancer Carcinoma Spheroids To Combination Therapy With Radiation And Dna-Pk Inhibitor: Growth Arrest Without A Change In Alpha/Beta Ratio

PurposeAgents that increase tumor radiosensitivity are of interest in improving outcomes in radiotherapy (XRT). DNA-PK inhibitors radiosensitize and alter cell adhesion proteins. We investigated combination radiation and a DNA-PK inhibitor in monolayers vs spheroids.Materials and methodsUsing HER2 positive mammary carcinoma cells, we investigated the impact of NU7441, a DNA-PK inhibitor, on irradiated monolayer and spheroid cultures. Colony formation assays were performed with monolayer culture cells and spheroids after irradiation with/without NU7441 (5 mu M).ResultsIn monolayer culture cells, alpha/beta increased from 3.0 +/- 0.2 Gy (XRT alone) to 6.9 +/- 0.2 Gy (XRT+NU7441). Corresponding alpha/beta values for cells obtained by disaggregating treated spheroids were 3.6 +/- 0.7 Gy (XRT alone) and 3.5 +/- 0.2 Gy (XRT+NU7441). However, spheroid survival was highly sensitive to NU7441 incubation. After 4 Gy XRT alone 75% of the irradiated spheroids remained intact; when NU7441 treatment was involved, 13% remained intact. No spheroids survived to 3 weeks at 6 Gy or more. The discrepancy between the minimal change in alpha/beta from cells derived from spheroids and the spheroid growth response was not related to poor penetration of NU7441.ConclusionsDNA-PK inhibitor NU7441 radiosensitized monolayer cells but not cells obtained from spheroids. NU7441 and radiation increased spheroid fragmentation.