Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth

Abstract

These data suggest that combined treatment with drugs that target EGFR and ErbB-2 might result in an efficient inhibition of tumor growth in those breast carcinoma patients whose tumors co-express both receptors.

Effects of the combined blockade of EGFR and ErbB-2 on signal transduction and regulation of cell cycle regulatory proteins in breast cancer cells

“…In agreement with these findings, co-expression of EGFR, ErbB-2 and ErbB-3 was also found to have a negative synergistic effect on patient outcome, independent of tumor size or lymph node status [9]. Different anti-EGFR agents, including the EGFR tyrosine kinase inhibitor (EGFR-TKI) gefitinib (ZD1839, Iressa), have shown to inhibit the growth of human breast carcinoma cells [10][11][12][13][14]. We and other research groups have demonstrated that breast cancer cell lines with high levels of expression of ErbB-2 are more sensitive to gefitinib as compared with ErbB-2-negative cells [11][12][13][14].…”

“…We and other groups have previously demonstrated that a synergistic anti-tumor effect occurs when breast cancer cells that co-express EGFR and ErbB-2 are treated with a combination of gefitinib and the anti-ErbB-2 monoclonal antibody trastuzumab [11][12][13]. In particular, we demonstrated that the two drugs have a strong synergism in breast cancer cells by using a wide range of concentrations of both drugs and isobolographic analysis [13].…”

“…The human breast cancer cell lines SK-Br-3 and BT-474 were obtained from the American Type Culture Collection (Rockville, MD, USA) and were cultured as previously described [13]. …”

“…In particular, we demonstrated that the two drugs have a strong synergism in breast cancer cells by using a wide range of concentrations of both drugs and isobolographic analysis [13]. Such combination failed to show significant activity in a phase I/II clinical trial [22].…”

“…Different anti-EGFR agents, including the EGFR tyrosine kinase inhibitor (EGFR-TKI) gefitinib (ZD1839, Iressa), have shown to inhibit the growth of human breast carcinoma cells [10][11][12][13][14]. We and other research groups have demonstrated that breast cancer cell lines with high levels of expression of ErbB-2 are more sensitive to gefitinib as compared with ErbB-2-negative cells [11][12][13][14]. However, clinical studies of gefitinib in breast cancer resulted in few clinical responses and in a disease control rate of approximately 10% [15][16][17].…”