BACKGROUND: We investigated the expression of the epidermal growth factor (EGF) network before and after castration in the prostate cancer xenograft CWR22 implanted in nude mice, and examined the effects of gefitinib (Iresssa, ZD1839), a new drug directed towards the EGF tyrosine kinase receptor (HER1) of the EGF network. METHODS: CWR22 prostate cancer xenografts were propagated in immunodeficient male mice. The expression of the growth factors and receptors in the EGF network was examined by real-time PCR analysis and ELISA at 0, 7, 14, and 30 days after castration, and the tumor growth was examined after treatment with gefitinib or placebo. RESULTS: A fraction of growth factors showed a steady increase in the mRNA expression reaching between fourfold and eightfold 30 days after castration, including amphiregulin (P < 0.005) and epiregulin (P < 0.001). ELISA for amphiregulin showed a fivefold increase 30 days after castration. Tumor bearing mice were castrated and treated with or without the HER1 tyrosine kinase inhibitor gefitinib. Tumor involution was significantly increased by castration plus gefitinib as compared to castration alone. CONCLUSIONS: Castration leads to adaptive increase in the concentrations of a subset of growth factors from the EGF network in the androgen sensitive CWR22 prostate cancer xenograft. Specific inhibition of the HER1 tyrosine kinase receptor significantly increases the tumor involution, and suggests that HER1 targeted drugs could be of therapeutic relevance in the treatment of advanced prostate cancer.
BACKGROUND: We investigated the expression of the epidermal growth factor (EGF) network before and after castration in the prostate cancer xenograft CWR22 implanted in nude mice, and examined the effects of gefitinib (Iresssa, ZD1839), a new drug directed towards the EGF tyrosine kinase receptor (HER1) of the EGF network. METHODS: CWR22 prostate cancer xenografts were propagated in immunodeficient male mice. The expression of the growth factors and receptors in the EGF network was examined by real-time PCR analysis and ELISA at 0, 7, 14, and 30 days after castration, and the tumor growth was examined after treatment with gefitinib or placebo. RESULTS: A fraction of growth factors showed a steady increase in the mRNA expression reaching between fourfold and eightfold 30 days after castration, including amphiregulin (P < 0.005) and epiregulin (P < 0.001). ELISA for amphiregulin showed a fivefold increase 30 days after castration. Tumor bearing mice were castrated and treated with or without the HER1 tyrosine kinase inhibitor gefitinib. Tumor involution was significantly increased by castration plus gefitinib as compared to castration alone. CONCLUSIONS: Castration leads to adaptive increase in the concentrations of a subset of growth factors from the EGF network in the androgen sensitive CWR22 prostate cancer xenograft. Specific inhibition of the HER1 tyrosine kinase receptor significantly increases the tumor involution, and suggests that HER1 targeted drugs could be of therapeutic relevance in the treatment of advanced prostate cancer.
Authors: Shaowei Li; Fumiko Takeuchi; Ji-An Wang; Qingyuan Fan; Toshi Komurasaki; Eric M Billings; Gustavo Pacheco-Rodriguez; Joel Moss; Thomas N Darling Journal: Proc Natl Acad Sci U S A Date: 2008-02-21 Impact factor: 11.205
Authors: Meghan S Vermillion; Rebecca L Ursin; Denise I T Kuok; Landon G Vom Steeg; Nicholas Wohlgemuth; Olivia J Hall; Ashley L Fink; Eric Sasse; Andrew Nelson; Roland Ndeh; Sharon McGrath-Morrow; Wayne Mitzner; Michael C W Chan; Andrew Pekosz; Sabra L Klein Journal: Biol Sex Differ Date: 2018-07-17 Impact factor: 5.027