Cisplatin and radiation sensitivity in human head and neck squamous carcinomas are independently modulated by glutathione and transcription factor NF-kappa B

Background. Response to neoadjuvant cisplatin-based chemotherapy has been u sed to predict overall response to chemoradiation therapy and to select pat ients with head and neck squamous cell carcinoma (HNSCC) for organ preserva tion therapy in NCI and VA cooperative group trials. However. differ ent mo lecular determinants have been reported to contribute to sensitivity of cel ls to cisplatin and radiation, including glutathione (GSH), and activation of nuclear factor-kappaB (NF-kappaB), a transcription factor that regulates cytoprotective genes. We have reported that NF-kappaB is constitutively ac tivated in HNSCC, but the relationship of NF-kappaB to GSH and to cisplatin and radiation sensitivity in HNSCC is unknown. Methods. We examined human HNSCC lines to define the relationship of cispla tin and radiation sensitivity to intracellular GSH and NF-kappaB and determ ined whether HNSCC could be sensitized to these modalities by lowering the concentration of glutathione with L-buthionine sulfoximine or inhibiting ac tivation of NF-kappaB by expression of a degradation-resistant mutant inhib itor-kappaB alpha. Results. Cisplatin resistance did not predict radiation resistance in three HNSCC call lines, UM-SCC-9, 11B, and, 38. Resistance to cisplatin correlat ed with intracellular GSH, and depletion of GSH by treatment with L-BSO sen sitized UM-SCC-9 cells to cisplatin but not radiation. conversely, radiatio n resistance was correlated with activation of NF-kappaB. Expression of a m utant Inhibitor-kappaB after gene transfer inhibited NF-kappaB and sensitiz ed UM-SCC-9 cells to radiation but not cisplatin. Conclusions. GSH and transcription factor NF-alphaB can contribute independ ently to cisplatin and radiation sensitivity of human HNSCC. These results highlight the need to define molecular determinants of chemotherapy and rad iation sensitivity for use in the selection of patients and as novel target s for therapy in future chemoradiation therapy trials for organ preservatio n in patients with HNSCC. (C) 2000 John Wiley & Sons, Inc.