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Iressa Has Potential in Tamoxifen-Resistant Cancer

Iressa Has Potential in Tamoxifen-Resistant Cancer

SAN FRANCISCO—Early research suggests that the epidermal growth
factor receptor (EGFR) inhibitor Iressa (ZD1839, investigational) may have
therapeutic potential in tamoxifen (Nolvadex)-resistant breast cancer,
according to a presentation at the 37th Annual Meeting of the American Society
of Clinical Oncology (ASCO abstract 282).

Although many estrogen-receptor-positive breast cancers respond initially to
tamoxifen, responses are frequently followed by tumor regrowth attributable to
acquired tamoxifen resistance, said J.M. Gee, PhD, Tenovus Centre for Cancer
Research, Cardiff, UK. The antiestrogen-resistant phase of the disease, she
said, is also associated with over-expression of EGFR and/or EGFR ligands.

Dr. Gee looked at tamoxifen-resistant (R-MCF-7) and wild-type
tamoxifen-sensitive (MCF-7) breast cancer cell lines. She found that, like
patients with acquired tamoxifen resistance, the R-MCF-7 cells showed markedly
elevated mRNA and protein expression of EGFR and HER-2, compared with the wild
type cells.

The model was further validated when it was seen that priming with exogenous
EGFR ligands increased activation of EGFR signaling elements and induced
substantial growth response, Dr. Gee said. Analysis showed that EGFR signaling
is critically important to the growth of R-MCF-7 breast cancer cells. Further
investigations showed that Iressa efficiently blocked activation of EGFR
signaling elements in the R-MCF-7 cells.

After 7 days, concentrations of 1 µM of Iressa in R-MCF-7 cells caused
complete inhibition of EGFR and almost total cell growth arrest (90%), reducing
cells in S phase and causing accumulation of cells in the G0 and G1 phase of
the cell cycle. Growth inhibitory effects in wild type cells were much lower
(15%).

Dr. Gee pointed out also that the growth inhibitory effects of Iressa on the
R-MCF-7 cells persisted for more than 6 months, indicating that the autocrine
EGFR loop is critical to the growth of tamoxifen-resistant cells, and that no
other mitogenic network is readily available to them when EGFR signaling is
blocked.

Experiments with dual treatment (Iressa plus tamoxifen) suggested further
utility. Treating wild type cells with tamoxifen alone caused substantial
growth arrest for 1 month followed by regrowth. After dual treatment, however,
there was no proliferation at 3 months. "You get superior cell growth
arrest and induction of apoptosis," she said.

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