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Biotech / Medical : Kosan BioSciences -- KOSN
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To: tuck who started this subject1/11/2004 10:46:51 AM
From: scaram(o)uche  Read Replies (1) of 933
 
Int J Radiat Biol. 2003 Dec;79(12):973-80.

Geldanamycin, an inhibitor of Hsp90, sensitizes human tumour cells to radiation.

Machida H, Matsumoto Y, Shirai M, Kubota N.

Department of Radiological Sciences Ibaraki Prefectural University of Health Sciences Ami-machi Ibaraki 300-0394 Japan.

Purpose: The effects of the heat shock protein 90 (Hsp90) inhibitor geldanamycin (GA) were examined on the radiosensitivity and signal transduction pathways in human tumour cell lines. Materials and methods: Two human cell lines, SQ-5 and DLD-1, derived from lung carcinoma and colon adenocarcinoma, respectively, were incubated for 16 h at 37 degrees C in medium containing 0.2 micro M GA. The cells were then irradiated with X-rays and incubated with GA for a further 8 h. Radiation sensitivity was determined by clonogenic assays and protein levels were examined by Western blotting. Results: GA radiosensitized both cell lines, but potentiated X-ray sensitivity more in SQ-5 than in DLD-1 cells. It was found that GA depleted EGFR and ErbB-2 in DLD-1 cells and depleted only ErbB-2 in SQ-5 cells. GA also reduced the expression of Akt and phosphorylated Akt (pAkt) expression in SQ-5 cells. In addition, the ratio (%) of apoptotic cells and poly [ADP-ribose] polymerase cleavage increased in SQ-5 but not in DLD-1 cells after exposure to GA and X-ray irradiation. The findings suggest that GA enhances the radiation sensitivity of human tumour cells by inhibiting the EGFR signal transduction system and the Akt signalling pathway. Conclusion: Targeting Hsp90 with GA provides a promising experimental strategy for radiosensitization of carcinoma.
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