TY - JOUR
T1 - Evaluation of novel epidermal growth factor receptor tyrosine kinase inhibitors
AU - Rae, James M.
AU - Lippman, Marc E.
N1 - Funding Information:
We are grateful to Dr David Fry for kindly providing us with the tyrosine kinase inhibitors and to Dr Jackie Pierce (NCI) for providing the 32D cells. This work was supported by a Specialized Project of Research Excellence Grant (Breast) from the National Cancer Institute (1P50CA58185).
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2004/1
Y1 - 2004/1
N2 - The epidermal growth factor system is a well characterized growth factor receptor pathway, the deregulation of which has been be associated with neoplastic growth. Overexpression or amplification of the epidermal growth factor receptor (EGFR) or one of its ligands has been linked with the malignant transformation of cells and is correlated with poor prognosis in patients. PD 153035, a quinazoline, has been shown to inhibit the tyrosine kinase activity of EGFR by blocking ATP binding (Fry et al., Science 265: 1093-1095, 1994). We set out to determine whether the growth inhibition caused by this agent and five related compounds is a direct result of the blocking of EGFR signaling. The effects on cell proliferation produced by these agents were tested on several tumor cell lines and EC50 values obtained. The EGF responsive cell lines A-431 and MDA-MB-468 exhibit EC50 values of 3 and 6.7 μM, respectively, for PD 153035 which was found to be the most potent. The agents were then tested for their ability to block the paradoxical high dose EGF induced inhibition of A-431 and MDA-MB-468 cell growth as well as EGF induced phosphorylation in A-431 cells. These compounds are able to completely block the effects of exogenously added EGF at 0.5 μM or less. However, higher doses (EC50's ≥ 2 μM) were needed to block the growth of human tumor cell lines potentially implicating a second site of action for these compounds.
AB - The epidermal growth factor system is a well characterized growth factor receptor pathway, the deregulation of which has been be associated with neoplastic growth. Overexpression or amplification of the epidermal growth factor receptor (EGFR) or one of its ligands has been linked with the malignant transformation of cells and is correlated with poor prognosis in patients. PD 153035, a quinazoline, has been shown to inhibit the tyrosine kinase activity of EGFR by blocking ATP binding (Fry et al., Science 265: 1093-1095, 1994). We set out to determine whether the growth inhibition caused by this agent and five related compounds is a direct result of the blocking of EGFR signaling. The effects on cell proliferation produced by these agents were tested on several tumor cell lines and EC50 values obtained. The EGF responsive cell lines A-431 and MDA-MB-468 exhibit EC50 values of 3 and 6.7 μM, respectively, for PD 153035 which was found to be the most potent. The agents were then tested for their ability to block the paradoxical high dose EGF induced inhibition of A-431 and MDA-MB-468 cell growth as well as EGF induced phosphorylation in A-431 cells. These compounds are able to completely block the effects of exogenously added EGF at 0.5 μM or less. However, higher doses (EC50's ≥ 2 μM) were needed to block the growth of human tumor cell lines potentially implicating a second site of action for these compounds.
KW - Epidermal growth factor
KW - Epidermal growth factor receptor
KW - Neoplastic growth
KW - Tyrosine kinase inhibitor
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U2 - 10.1023/B:BREA.0000010702.10130.29
DO - 10.1023/B:BREA.0000010702.10130.29
M3 - Article
C2 - 14997040
AN - SCOPUS:0742304061
VL - 83
SP - 99
EP - 107
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
SN - 0167-6806
IS - 2
ER -