Molecular pathways that modify tumor radiation response

Aberrant expression of signal transduction molecules in pathways controllin g cell survival, proliferation, death, or differentiation are a common feat ure of all tumors. The identification of the molecules that are involved al lows the development of novel tumor-specific strategies. Not surprisingly, targeting these pathways often also results in radiosensitization. The effi cacy of such directed therapies may, however, be limited by the heterogenei ty and the multiple mutations that are associated with the cancerous state. A more robust alternative may be to target global mechanisms of cellular c ontrol. The ubiquitin/proteasome degradation pathway is one candidate for s uch therapeutic intervention. This pathway is the main posttranscriptional mechanism that controls levels of many short-lived proteins involved in reg ulation of cell cycle progression, DNA transcription, DNA repair, and apopt osis. Many of these proteins are involved in various malignancies and/or ra diation responses. In recent years, proteasome inhibitors have gained inter est as a promising new group of antitumor drugs. PS-341, a reversible inhib itor of proteasome chymotryptic activity, is currently being tested in phas e I clinical trials. In this study, we show that proteasome inhibition by P S-341 can alter cellular radiosensitivity in vitro and in vivo, in addition to having direct antitumor effects.