Background
Overactivity of the epidermal growth factor receptor-associated tyrosine kinase (EGFR) has been associated with cancer development and progression, including cell proliferation, apoptosis, angiogenesis, and metastatic spread.1 PD 153035 is a highly potent, reversible inhibitor of the EGFR (Ki = 5.2 pM; IC50 = 29 pM).2 It has been shown to rapidly suppress autophosphorylation of EGFR in ?broblasts and human epidermoid carcinoma cells, as well as to selectively block EGF-mediated cellular processes, including mitogenesis and early gene expression.3,4
1.Ciardiello, F., and Tortora, G.A novel approach in the treatment of cancer: Targeting the epidermal growth factor receptorClin. Cancer Res.7(10)2958-2970(2001)
2.Fry, D.W., Kraker, A.J., McMichael, A., et al.A specific inhibitor of the epidermal growth factor receptor tyrosine kinaseScience265(5175)1093-1095(1994)
3.Bos, M., Mendelsohn, J., Kim, Y.M., et al.PD153035, a tyrosine kinase inhibitor, prevents epidermal growth factor receptor activation and inhibits growth of cancer cells in a receptor number-dependent mannerClin. Cancer Res.3(11)2099-2106(1997)
4.Rae, J.M., and Lippman, M.E.Evaluation of novel epidermal growth factor receptor tyrosine kinase inhibitorsBreast Cancer Res. Treat.83(2)99-107(2004)
Protocol
Cell experiment: | Different EGF receptor-overexpressing cell lines (A43 1, Difi, MDA-MB-468, MDA-MB-231, DU145, SiHa, C4i, and MEl 80) are treated with PD153035 at increasing concentrations of 0.125-2.5 p.M. Growth inhibitory effect in monolayer cell culture is assessed[3]. |
Animal experiment: | Mice: Mice are injected with PD153035 (80 mg/kg) or vehicle and rumors are excised at 20 minutes and 180 minutes and extracts are prepared. Two mice are used for each time point and the experiment is repeated four times. Within each of the four experiments ANOVA is used to compare the inhibition by PD 153035 of the EGF-stimulation[3]. |
参考文献: [1]. Bridges AJ, et al. Tyrosine kinase inhibitors. 8. An unusually steep structure-activity relationship for analogues of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a potent inhibitor of the epidermal growth factor receptor. J Med Chem. 1996 Jan 5;39(1):267-76.
[2]. Fry DW, et al. A specific inhibitor of the epidermal growth factor receptor tyrosine kinase. Science. 1994 Aug 19;265(5175):1093-5.
[3]. Bos M, et al. PD153035, a tyrosine kinase inhibitor, prevents epidermal growth factor receptoractivation and inhibits growth of cancer cells in a receptor number-dependent manner. Clin Cancer Res. 1997 Nov;3(11):2099-106.
[4]. Kunkel MW, et al. Inhibition of the epidermal growth factor receptor tyrosine kinase by PD153035 in human A431 tumors in athymic nude mice. Invest New Drugs. 1996;13(4):295-302. |
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