Sensitivity to topoisomerase I inhibitors and cisplatin is associated withepidermal growth factor receptor expression in human cervical squamous carcinoma ME180 sublines
Yh. Ling et al., Sensitivity to topoisomerase I inhibitors and cisplatin is associated withepidermal growth factor receptor expression in human cervical squamous carcinoma ME180 sublines, CANC CHEMOT, 47(6), 2001, pp. 473-480
The relationship between expression and function of the epidermal growth fa
ctor (EGF) family of receptors and chemosensitivity remains controversial.
We studied the chemosensitivity to various anticancer agents of human cervi
cal squamous carcinoma ME 180 cells, and two resistant subclones, ME180/TNF
and ME180/Pt, which also differ in their EGF receptor (EGFR) expression. C
ompared with ME180 cells, EGFR is overexpressed sixfold in ME180/TNF cells
and is barely detectable in ME180/Pt cells. Cell cycle analysis by flow cyt
ometry and BrdU incorporation into DNA showed a correlation between EGFR ex
pression and percentage of cells in S phase and active DNA replication (35%
in high EGFR-expressing ME180/TNF cells, 19% in non-EGFR-expressing ME180/
Pt cells and 23% in parental, intermediate-level EGFR-expressing ME180 cell
s). By MTT assay and compared with parental, intermediate-level EGFR-expres
sing ME180 cells, high EGFR-expressing ME180/TNF cells had a three- to four
fold increased sensitivity to cisplatin, camptothecin (CPT), and topotecan,
and low EGFR-expressing ME180/Pt cells had a five- to ninefold reduced sen
sitivity to the same agents. In contrast, the degree of cross-resistance wi
th the topoisomerase II inhibitors doxorubicin and etoposide was minimal an
d the pattern of sensitivity to the anti-microtubulin agents vinblastine an
d paclitaxel was different, with a two- to fourfold decreased sensitivity i
n the high EGFR-expressing ME180/TNF cells and only a 1.5-fold decreased se
nsitivity in the low EGFR-expressing ME180/Pt cells. Neither alterations in
intracellular CPT levels nor changes in topoisomerase I expression or acti
vity, measured as ability to form DNA-protein complexes, were found to expl
ain the differences in sensitivity to CPT among the three cell lines. Go-tr
eatment with CP358774, a specific EGFR tyrosine kinase inhibitor, reduced t
he enhanced sensitivity of high EGFR-expressing ME180/ TNF cells to the val
ues observed in intermediate EGFR-expressing ME180 cells, but only reduced
modestly the sensitivity of intermediate expressing ME180 cells. As a resul
t, the resistance index of low EGFR-expressing ME180/Pt cells compared with
intermediate EGFR-expressing ME180 cells was reduced only from five- to fo
urfold for cisplatin and from seven- to fourfold for CPT when ME180 cells w
ere exposed to CP358774. CP358774 did not affect the sensitivity to either
agent in low EGFR-expressing ME180/Pt cells. These results provide evidence
that changes in EGFR expression or function may play a role in determining
chemosensitivity to platinum and topoisomerase I poisons in some human tum
or systems, and that the EGFR-related changes in chemosensitivity may vary
depending on the level of EGFR expression and/or function.