SAN ANTONIOZD1839 (or Iressa), an orally active,
selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor,
slows proliferation of cancer cells that overexpress EGFR and erbB2 (also known
as HER-2/neu), according to a study reported by Neil G. Anderson, PhD, of the
University of Manchester.
Accumulating research suggests that EGFR plays a role in cell
proliferation, invasion, metastasis, and tumor cell survival via multiple
signaling pathways. In human tumors, EGFR overexpression is associated with
high-grade lesions, invasiveness, and reduced disease-free and overall
survival, Dr. Anderson said at the San Antonio Breast Cancer Symposium.
EGFR forms heterodimers with other members of the erb (HER)
family, notably erbB2 (HER-2), he said. These heterodimers are believed to
induce more intense and prolonged signalingthrough the ras-MAP kinase
(ras-MAPK) pathway, for examplethereby inducing greater effects on
proliferation in these tumor cells (see Figure).
ZD1839 has been shown to block signal transduction pathways
implicated in the proliferation and survival of cancer cells.
"Because EGFR forms heterodimers with erbB2, we
hypothesized that inhibition of EGFR might have an effect on cancer cells that
overexpress erbB2," Dr. Anderson said. "The aim of our study was to
investigate the effects of EGFR blockade with Iressa on the proliferation of
EGFR-positive cancer cells that co-express various levels of erbB2."
An initial in vitro experiment evaluated the effects of ZD1839
on a variety of cancer cell lines. The cell lines were classified according to
their relative degrees of EGFR and erbB2 expression: high EGFR, relatively low
erbB2 expression; high erbB2 and low-to-medium EGFR expression; and relatively
low expression of both receptors.
ZD1839 inhibited proliferation in all the cell lines tested. In
a high EGFR/low erbB2-expressing breast cancer cell line (MDA-MB231) and a high
erbB2/low EGFR-expressing ovarian cancer cell line (SKOV3), ZD 1839 induced
around 60% inhibition. In the three high erbB2-overexpressing cell lines
tested, inhibition ranged from about 30% to 80%.
ZD1839 was then tested against MDA-MB231 cells and SKOV3 cells
grown in nude mice. The cells were established as tumors and grown for 14 or 21
days. ZD1839 was then administered at a daily dose of 75 mg/kg for 14 days.
The agent severely restricted the growth of the MDA-MB231
cells, which overexpress EGFRwith an approximately 70% reduction of tumor
growth after 14 days, Dr. Anderson said. "In the SKOV3
erbB2-overexpressing cell line, the effect was not as great, but we did get a
significant reduction in tumor growth, approximately 30%, after 14 days’
treatment," he said.
The researchers also evaluated ZD1839’s effects on the
activation status of ERK MAP kinase in the tumors. Treatment led to an
"almost complete wipeout" of two isomers of ERK MAP in the MDA-MB231
cells and significantly inhibited the activation of these enzymes in the
erbB2-overexpressing SKOV3 cells.
"Overall, our results suggest that Iressa is a strong
inhibitor of EGF receptor activity, thus blocking signaling downstream of these
complexes," Dr. Anderson said. "But it also appears to be able to
block signaling downstream of EGFR-erbB2 heterodimers. And, as these are more
potent signaling modules, the effect on downstream markers, such as
proliferation, is likely to be quite large."
The study results, he added, suggest that ZD1839 has
therapeutic potential for EGFR-positive cancers, whether or not they