Hans-Joachim Ochel1, Günther Gademann. 1. Clinic for Radiation Therapy, Medical Faculty, Otto von Guericke University, Leipziger Strasse 44, 39120 Magdeburg, Germany. hans-joachim.ochel@medizin.uni-magdeburg.de
Abstract
PURPOSE: Benzoquinone-ansamycins were the first compounds characterized with the ability to inhibit the function of heat shock protein 90 and its related family members. We investigated the composite effect of ionizing radiation and of these novel substances on the survival of malignant cells. METHODS: PC-3M prostate carcinoma cells were treated in vitro with increasing radiation doses in the presence or absence of Hsp90-active and Hsp90-inactive benzoquinone-ansamycins. Cytotoxicity was determined by the crystal violet dissolution assay. RESULTS: Twenty-four hour treatment with increasing geldanamycin doses (10 nM-1 microM) reduced cellular survival by 1.5 logs for all drug dose levels. Concomitant irradiation with a single fraction of 3 Gy reduced cellular survival by 2 logs, independently of drug dose. The treatment with 100 nM geldanamycin for 24 h combined with ionizing radiation (1-5 Gy) during the first hour of drug exposure reduced cellular survival by 1.5-2 logs depending on radiation-energy dose level, while no changes in cell survival were detectable with equimolar geldampicin, a benzoquinone-ansamycin known not to inhibit Hsp90. CONCLUSIONS: The inhibition of Hsp90 and the concomitant exposure to ionizing radiation decrease cellular survival of malignant cells. These data contribute to laying the foundation for the translational use of Hsp90 inhibitors in the multimodal therapy of cancer.
PURPOSE:Benzoquinone-ansamycins were the first compounds characterized with the ability to inhibit the function of heat shock protein 90 and its related family members. We investigated the composite effect of ionizing radiation and of these novel substances on the survival of malignant cells. METHODS: PC-3M prostate carcinoma cells were treated in vitro with increasing radiation doses in the presence or absence of Hsp90-active and Hsp90-inactive benzoquinone-ansamycins. Cytotoxicity was determined by the crystal violet dissolution assay. RESULTS: Twenty-four hour treatment with increasing geldanamycin doses (10 nM-1 microM) reduced cellular survival by 1.5 logs for all drug dose levels. Concomitant irradiation with a single fraction of 3 Gy reduced cellular survival by 2 logs, independently of drug dose. The treatment with 100 nM geldanamycin for 24 h combined with ionizing radiation (1-5 Gy) during the first hour of drug exposure reduced cellular survival by 1.5-2 logs depending on radiation-energy dose level, while no changes in cell survival were detectable with equimolar geldampicin, a benzoquinone-ansamycin known not to inhibit Hsp90. CONCLUSIONS: The inhibition of Hsp90 and the concomitant exposure to ionizing radiation decrease cellular survival of malignant cells. These data contribute to laying the foundation for the translational use of Hsp90 inhibitors in the multimodal therapy of cancer.
Authors: David B Solit; Fuzhong F Zheng; Maria Drobnjak; Pamela N Münster; Brian Higgins; David Verbel; Glenn Heller; William Tong; Carlos Cordon-Cardo; David B Agus; Howard I Scher; Neal Rosen Journal: Clin Cancer Res Date: 2002-05 Impact factor: 12.531