PURPOSE: Interaction of 17-allylamino-17-demethoxygeldanamycin (17-AAG) with heat shock protein 90 results in proteasomal degradation of many proteins, including Her-2-neu, with subsequent decreased expression of insulin-like growth factor binding protein-2 (IGFBP-2). Concentrations of both IGFBP-2 and Her-2 extracellular domain (Her-2 ECD) in sera of mice bearing BT474 human breast cancer xenografts decrease after 17-AAG treatment. We investigated whether this phenomenon occurred in patients. MATERIALS AND METHODS: Eight to 15 plasma samples were obtained between 0 and 72 h from 27 patients treated with single-agent 17-AAG at doses between 10 and 307 mg/m(2) and 18 patients treated with 17-AAG at doses between 220 and 450 mg/m(2) combined with 70 to 75 mg/m(2) of docetaxel. Pretreatment plasma samples were also obtained from 12 healthy volunteers. Plasma IGFBP-2 and Her-2 ECD concentrations were quantitated by ELISA. RESULTS: Pretreatment plasma IGFBP-2 concentrations in patients (171 +/- 116 ng/mL) were 2-fold higher than those in healthy volunteers (85 +/- 44 ng/mL; P < 0.05). Following 17-AAG treatment, there were no consistent dose-dependent or time-dependent changes in plasma IGFBP-2 and Her-2 ECD concentrations. IGFBP-2 concentrations decreased by >or=40% in 8 patients, increased 2- to 5-fold in 8 patients, and remained essentially unchanged in 29 patients. Her-2 ECD concentrations decreased by >or=40% in 10 patients, increased 1.5- to 5-fold in 2 patients, and remained essentially unchanged in 25 patients. CONCLUSIONS: As previously reported, IGFBP-2 concentrations in plasma of cancer patients are significantly higher than those in healthy volunteers. In contrast to a mouse model, 17-AAG treatment was not consistently associated with decreases in IGFBP-2 or Her-2 ECD concentrations in patient plasma.
PURPOSE: Interaction of 17-allylamino-17-demethoxygeldanamycin (17-AAG) with heat shock protein 90 results in proteasomal degradation of many proteins, including Her-2-neu, with subsequent decreased expression of insulin-like growth factor binding protein-2 (IGFBP-2). Concentrations of both IGFBP-2 and Her-2 extracellular domain (Her-2 ECD) in sera of mice bearing BT474 humanbreast cancer xenografts decrease after 17-AAG treatment. We investigated whether this phenomenon occurred in patients. MATERIALS AND METHODS: Eight to 15 plasma samples were obtained between 0 and 72 h from 27 patients treated with single-agent 17-AAG at doses between 10 and 307 mg/m(2) and 18 patients treated with 17-AAG at doses between 220 and 450 mg/m(2) combined with 70 to 75 mg/m(2) of docetaxel. Pretreatment plasma samples were also obtained from 12 healthy volunteers. Plasma IGFBP-2 and Her-2 ECD concentrations were quantitated by ELISA. RESULTS: Pretreatment plasma IGFBP-2 concentrations in patients (171 +/- 116 ng/mL) were 2-fold higher than those in healthy volunteers (85 +/- 44 ng/mL; P < 0.05). Following 17-AAG treatment, there were no consistent dose-dependent or time-dependent changes in plasma IGFBP-2 and Her-2 ECD concentrations. IGFBP-2 concentrations decreased by >or=40% in 8 patients, increased 2- to 5-fold in 8 patients, and remained essentially unchanged in 29 patients. Her-2 ECD concentrations decreased by >or=40% in 10 patients, increased 1.5- to 5-fold in 2 patients, and remained essentially unchanged in 25 patients. CONCLUSIONS: As previously reported, IGFBP-2 concentrations in plasma of cancerpatients are significantly higher than those in healthy volunteers. In contrast to a mouse model, 17-AAG treatment was not consistently associated with decreases in IGFBP-2 or Her-2 ECD concentrations in patient plasma.
Authors: Shivaani Kummar; Martin E Gutierrez; Erin R Gardner; Xiaohong Chen; William D Figg; Maria Zajac-Kaye; Min Chen; Seth M Steinberg; Christine A Muir; Mary Ann Yancey; Yvonne R Horneffer; Lamin Juwara; Giovanni Melillo; S Percy Ivy; Maria Merino; Len Neckers; Patricia S Steeg; Barbara A Conley; Giuseppe Giaccone; James H Doroshow; Anthony J Murgo Journal: Eur J Cancer Date: 2009-11-27 Impact factor: 9.162
Authors: Komal Jhaveri; Stefan O Ochiana; Mark Ps Dunphy; John F Gerecitano; Adriana D Corben; Radu I Peter; Yelena Y Janjigian; Erica M Gomes-DaGama; John Koren; Shanu Modi; Gabriela Chiosis Journal: Expert Opin Investig Drugs Date: 2014-03-26 Impact factor: 6.206