Frage an Prof. Wust

**Prof. Wust** · 22.10.2002, 19:58

RE: Frage an Prof. Wust

Iressa ist ein Tyrosinkinase Inhibitor (s.u.). Der Angriffspunkt ist jedoch meines Wissens nicht vollkommen identisch mit dem des Antikörpers Herceptin, der an dem Transmembran-Protein HER-2 neu angreift (obwohl auch dieser Thyrosinkinase-Aktivität aufweist). Bezüglich Ihrer speziellen Frage nach Kreuzresistenzen, muß man das wohl in den klinischen Studien abklären.

ZD1839 (IRESSA), an EGFR-selective tyrosine kinase inhibitor, enhances taxane activity in bcl-2 overexpressing, multidrug-resistant MCF-7 ADR human breast cancer cells.
AU: Ciardiello,-Fortunato; Caputo,-Rosa; Borriello,-Gaetano; Del-Bufalo,-Donatella; Biroccio,-Annamaria; Zupi,-Gabriella; Bianco,-A-Raffaele; Tortora,-Giampaolo
AD: Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Universita di Napoli Federico II, Naples, Italy. [email protected]
SO: Int-J-Cancer. 2002 Mar 20; 98(3): 463-9
AB: Constitutive bcl-2 overexpression increases the tumorigenic and metastatic potential of doxorubicin-resistant, estrogen-independent, MCF-7 ADR human breast cancer cells. We evaluated the sensitivity to taxanes (paclitaxel, docetaxel and IDN 5109) of 2 bcl-2-overexpressing MCF-7 ADR clones and control neomycin-transfected MCF-7 ADR neo cells. The 2 bcl-2-overexpressing MCF-7 ADR clones were relatively resistant to all 3 taxanes, whereas the MCF-7 ADR neo cells were relatively resistant to paclitaxel and docetaxel, but sensitive to IDN 5109. We found that both MCF-7 ADR neo and bcl-2-overexpressing MCF-7 ADR clones express high levels of the epidermal growth factor receptor (EGFR) and its ligand, transforming growth factor-alpha (TGF-alpha). Therefore, we tested the growth inhibitory effect of ZD1839 (Iressa, AstraZeneca, Macclesfield, UK), an orally active, selective EGFR tyrosine kinase inhibitor (EGFR-TKI) that is in clinical development. ZD1839 inhibited the growth in soft agar of all 3 clones in a dose-dependent manner (IC(50) of approximately 0.1 microm). This effect was accompanied by a dose-dependent inhibition of EGFR tyrosine autophosphorylation and of the production of TGF-alpha, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). To determine whether the blockade of EGFR signaling might affect the sensitivity of bcl-2-overexpressing MCF-7 ADR cells to taxanes, cells were treated with ZD1839 in combination with paclitaxel, docetaxel or IDN 5109, and dose-dependent cooperative growth inhibition as well as apoptosis potentiation were observed. Combined treatment with IDN 5109 and ZD1839 also resulted in a significant inhibition of bcl-2 expression in bcl-2-overexpressing MCF-7 ADR cells. These results demonstrate the ability of ZD1839 to overcome taxane resistance in a model of hormone-independent, multidrug-resistant, human breast cancer. Copyright 2002 Wiley-Liss, Inc.

Prospects for combining hormonal and nonhormonal growth factor inhibition.
AU: Wakeling,-A-E; Nicholson,-R-I; Gee,-J-M
AD: Cancer Research Department, AstraZeneca Pharmaceuticals, Macclesfield, Cheshire, United Kingdom. [email protected]
SO: Clin-Cancer-Res. 2001 Dec; 7(12 Suppl): 4350s-4355s; discussion 4411s-4412s
AB: In patients with estrogen receptor (ER)-negative disease or ER+ hormone-resistant disease, the dominant influence on tumor cell growth is growth factors, e.g., epidermal growth factor (EGF), heregulins, and insulin-like growth factors acting through specific receptor tyrosine kinases at the cell surface. This superfamily of ligand-activated growth factor receptors triggers cascades of biochemical signals that influence tumor cell motility, invasiveness, angiogenesis, and survival, as well as proliferation. In breast tumors, expression of epidermal growth factor receptor (EGFR) and/or erbB2 is associated with poor prognosis; the therapeutic utility of blocking these receptors has been established using trastuzumab (Herceptin), a monoclonal antibody that blocks erbB2 signaling. An alternative therapeutic approach is offered by small molecule inhibitors of EGFR-TK, exemplified by ZD1839 (Iressa), a potent and selective EGFR-TK inhibitor. Resistance to tamoxifen is associated with up-regulation of the EGFR-TK pathway and mitogen-activated protein kinase activity is substantially increased in tamoxifen-resistant MCF-7 cells. ZD1839 treatment of tamoxifen-resistant MCF-7 cells blocks mitogen-activated protein kinase activity. Furthermore, treatment of wild-type MCF-7 cells with tamoxifen and ZD1839 prevents development of tamoxifen resistance. These data support the potential clinical utility of ZD1839 in tamoxifen-resistant breast cancer and suggest the possibility of preventing resistance by the early use of combination ZD1839 with antiestrogenic agents such as tamoxifen or ICI 182,780.

Frage an Prof. Wust

Frage an Prof. Wust

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