Protein kinase C PKC promotes cell survival in response to ionizing radiation in a variety of experimental models including human carcinoma, human glioblastoma, and transformed mouse embryo fibroblast cell lines. The purpose of this project is to enhance radiation-induced mammary tumor cell death by inhibition of specific PKC isoforms. Antisense oligonucleotides have been introduced into human breast tumor cell lines to selectively inhibit PKC isoforms. MDA-MB- 231 and MCF-7 cells treated with oligonucleotides directed against PKC isoforms 8 and zeta exhibited impaired survival in response to 5 .6Gy gamma radiation as measured by mitochondrial metabolism of tetrazolium dye. PKC 8 and zeta oligonucleotides were shown to selectively deplete PKC 8 and zeta proteins from cell extracts. Furthermore, a selective PKC 8 inhibitor, rottlerin, impaired survival of cells treated with a therapeutically relevant dose of radiation 1 .5Gy. Treatment of MDA-MB-23 1 cells prior to low dose radiation exposure with PKC 8 oligonucleotide significantly impaired cell survival. The conclusion of this work is that PKC 8 and PKC zeta act as a pro-survival factors in human breast tumor cells in vitro. These findings suggest that down-regulation of PKC 8 and PKC zeta may be a useful approach to radiosensitization in mammary tumors.