Chemotherapy employing
paclitaxel and
docetaxel is widely used for treating early-stage
breast cancer and
metastasis, which is frequently associated with overexpression of
epidermal growth factor receptor (EGFR) and resistance to apoptosis.
ZD6474, a dual
tyrosine kinase inhibitor of EGFR and VEGFR, inhibits cell proliferation of solid
tumors, including breast. Phase III clinical trials using
ZD6474 in
non-small cell lung carcinoma when combined with standard
chemotherapy appear promising. In order to improve the
antineoplastic activity of
paclitaxel, we presently investigated the effects of
ZD6474 in combination with
paclitaxel in EGFR and VEGFR expressing human
breast cancer cell lines MCF-7 and MDA-MB-231.
ZD6474 synergistically decreased cell viability when used in combination with
paclitaxel.
ZD6474 inhibited
cyclin D1 and
cyclin E expression and induced p53 expression when combined with
paclitaxel. The combination of
ZD6474 with
paclitaxel versus either agent alone also more potently down-regulated the antiapoptotic bcl-2
protein, up-regulated pro-apoptotic signaling events involving expression of bax, activation of
caspase-3 and
caspase-7 proteins, and induced
poly(ADP-ribose) polymerase resulting in apoptosis.
ZD6474 combined with
paclitaxel inhibited anchorage-independent colony formation and invasion of
breast cancer cells in vitro as compared to either single agent, indicating a potential involvement of altered expression and reorganization of
cytoskeletal proteins in combinatorial treated
breast cancer cells. Collectively, our studies indicate that incorporating an anti-EGFR plus VEGFR strategy (
ZD6474) with
chemotherapy (
paclitaxel), where clinical studies of dose-intensive
paclitaxel therapy are currently in progress, may be more effective in treating patients with locally advanced or metastatic
breast cancer than either approach alone.