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Heat shock protein 90 (Hsp90) is a molecular chaperone that promotes the conformational maturation of numerous client proteins, many of which play critical roles in tumor cell growth and survival. The ansamycin-based Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) is currently in Phase III clinical testing. However, 17-AAG is difficult to formulate and associated with dose-limited toxicity issues. A fully synthetic and bioavailable Hsp90 inhibitor, BIIB021, was evaluated for antitumor activity in a variety of head and neck squamous cell carcinoma (HNSCC) cell lines and HNSCC xenograft models, either as a single agent or in combination with fractionated radiation and the results were compared with that of 17-AAG. BIIB021 showed strong antitumor activity, comparable with, and in certain instances, superior to 17-AAG. BIIB021 enhanced the in vitro radiosensitivity of HNSCCA cell lines with a corresponding reduction in the expression of key radioresponsive proteins, increased apoptotic cells and enhance G2 arrest. In xenograft studies, BIIB021 exhibited a strong antitumor effect outperforming 17-AAG, either as a single agent and or in combination with radiation, thereby improved the efficacy of radiation. These results suggest that this synthetic and bioavailable Hsp90 inhibitor affects multiple pathways involved in tumor development and progression in the HNSCC setting and may represent a better strategy for the treatment of HNSCC patients, either as a monotherapy or a radiosensitizer. Furthermore, it also demonstrates the benefits of using preclinical models of chemosensitization to radiotherapy to explore clinically relevant radiation dosing schemes.