INHIBITION OF GROWTH OF PRIMARY HUMAN TUMOR-CELL CULTURES BY A 4-ANILINOQUINAZOLINE INHIBITOR OF THE EPIDERMAL GROWTH-FACTOR RECEPTOR FAMILY OF TYROSINE KINASES
Bc. Baguley et al., INHIBITION OF GROWTH OF PRIMARY HUMAN TUMOR-CELL CULTURES BY A 4-ANILINOQUINAZOLINE INHIBITOR OF THE EPIDERMAL GROWTH-FACTOR RECEPTOR FAMILY OF TYROSINE KINASES, European journal of cancer, 34(7), 1998, pp. 1086-1090
The epidermal growth factor receptor (EGFR) is thought to mediate the
action of the mitogens EGF and tumour growth factor-alpha (TGF-alpha)
in a variety of cancers, including those of the lung, breast and ovary
. A number of new selective inhibitors of EGFR tyrosine kinase have no
w been developed as potential new antitumour agents. We used a potent
inhibitor of this tyrosine kinase, 6-amino-4- [(3-bromophenyl)amino]-7
-(methylamino) quinazoline (SN 25531; PD 156273), to determine the res
ponses of primary cultures derived from patients with cancer of the lu
ng, ovary, breast, cervix and endometrium. Cells were cultured in 96-w
ell plates and proliferation assessed by incorporation of H-3-thymidin
e. Measured growth inhibitory concentrations IC50 values) varied from
1 nM to 14 mu M with a 1000-fold differential between sensitive and re
sistant cultures. Results were compared with rates of proliferation, e
stimated using a paclitaxel-based method. We also measured the IC50 va
lues for the tyrosine kinase inhibitor using a number of established h
uman cell lines, and compared them with EGFR content using fluorescent
antibody staining and flow cytometry. The presence of EGFR was found
to be necessary, but not sufficient, for in vitro response. Only a sma
ll number of cell lines (3 of 7 for lung, 1 of 7 for ovarian, 2 of 3 s
quamous cell and 0 of 12 for melanoma) were sensitive to the tyrosine
kinase inhibitor. In contrast, 40 of the 50 primary cultures (includin
g 14 of 15 lung cancer samples and 14 of 19 ovarian cancer samples) we
re sensitive. (C) 1998 Elsevier Science Ltd. All rights reserved.