A novel poly(ADP-ribose) polymerase inhibitor, ABT-888, radiosensitizes malignant human cell lines under hypoxia.

摘要: The chemo- and radioresponse of tumor cells can be determined by genetic factors (e.g., those that modify cell cycle arrest, DNA damage repair or death) microenvironmental factors, such as hypoxia. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme rapidly recognizes binds to breaks facilitate strand break repair. Pre-clinical data suggest PARP inhibitors (PARPi) may potentiate the effects radiotherapy chemotherapy. However, it unclear whether PARPi are effective against hypoxic cells. We therefore tested role for novel PARPi, ABT-888, radiosensitizing agent under conditions. Using human prostate (DU-145, 22RV1) non-small lung (H1299) cancer lines, we observed ABT-888 inhibited both recombinant activity intracellular (86% 92% decrease in all 3 lines following 2.5 microM treatment). was toxic oxic When combined with ionizing radiation (IR), clonogenic survival decreased 40-50% Under acute hypoxia, radiosensitized malignant level similar radiosensitivity. To our knowledge, this first study demonstrate inhibition sensitize combination IR-PARPi has potential improve therapeutic ratio radiotherapy.