Activation of diverse pathways to apoptosis by (125)IdUrd and gamma-photon exposure.

Purpose: To delineate the mechanisms underlying induction of apoptosis in malignant cells irradiated by DNA-incorporated iodine-125 or gamma-photons.

Materials And Methods: Human tumor cells (RKO, LS174T, TE671, and MCF7) were irradiated by DNA-incorporated 5-[125I]iodo-2'-deoxyuridine (125IdUrd) or by gamma-photons. Clonogenic survival was determined by the colony-forming assay. Caspase-3 induction was measured with a fluorogenic substrate assay, and DNA fragmentation was determined by ligation-mediated polymerase chain reaction. DNA arrays were used to assess the expression of the B-cell lymphoma/leukaemia-2 (Bcl-2) family and related genes in RKO cells and in caspase-3-gene-defective MCF7 cells.

Results: After 125IdUrd or y-photon exposure, the highest induction of caspase-3 was observed in the radiation-sensitive cell lines (RKO and LS174T). DNA fragmentation was prominent in the radiosensitive cells and undetectable in TE671 (125IdUrd and gamma-photons) and MCF7 (125IdUrd only) cells. Exposure of RKO and MCF7 cells to 125I decay led to up-regulation of several pro-apoptotic and antiapoptotic Bcl-2 family genes whereas y-irradiation produced minimal activation.

Conclusions: Apoptosis generated by a DNA-incorporated Auger electron emitter is induced through the mitochondrial/caspase-3-mediated pathway and correlates with cellular radiosensitivity. Apoptosis caused by y-radiation can be signaled without activation of Bcl-2 family genes, and DNA fragmentation occurs with or without caspase-3 activation.