Effects of epithelial growth factor receptor (EGFR) kinase inhibitors on genetically reconstituted mouse mammary
Daniel R Roth1, Danielle Roman, Robert Cozens
1Department of Pathology, Preclinical Safety, Novartis AG, Basel, Switzerland.
Unlabelled:
The aim of the study was to determine the effects of a specific epithelial growth factor Receptor kinase inhibitor (EGFR-KI) and Taxol on tumor growth in a novel tumor model.
Material & Methods:
A genetically engineered tumor model which uses "transgenic" organs in immune competent mice was used. NeuT-transfected immortalized HC11 epithelial cells and primary mouse mammary epithelial cells have been transplanted into the gland-free mammary fat pad of female BALB/c mice. Mammary tumors developed after a latency period of three to four weeks. The mice were thereafter daily orally treated over a 19 or 22-day period with 0, 38, 75, 2 x 75 mg/kg body weight (b.w.) EGFR-KI (n: 7-9 per group) or intravenously with 10 mg/kg b.w. Taxol. After necropsy the histopathological evaluation of the tumors was performed in a coded manner. The proliferation activity of tumor cells was analyzed by laser scanning cytometry (LSC) using anti-Ki67-antibodies.
Results:
Oral Treatment with EGFR-KI in this transgenic organ model showed clear antitumor efficacy in a dose-dependent manner in the range between 38 and 75 mg/kg b.w. This antiproliferative effect appears to be minimally increased at 75 mg/kg/day twice per day. For all treatments a strong correlation between the biological behavior of the tumor, histopathology and cell proliferation could be established. In contrast, treatment with Taxol showed no significant reduction of tumor growth or cell proliferation in this model. This new transgenic organ model comprising histopathological evaluation and cell proliferation analysis appears to be a suitable test system for drug candidates that affect specific biochemical pathways. It may have greater predictive nature for clinical effects in humans as compared to conventional tumor models because of its c-erb B2 gene overexpression.
Insights
A novel transgenic organ model demonstrated that an epithelial growth factor Receptor kinase inhibitor (EGFR-KI) effectively reduced tumor growth dose-dependently. Taxol showed no significant effect in this new preclinical tumor model.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Development of novel preclinical tumor models is crucial for evaluating drug efficacy.
- Transgenic organ models offer potential for increased predictive value in drug discovery.
- Understanding the effects of targeted therapies like EGFR inhibitors is essential in cancer research.
Purpose of the Study:
- To assess the antitumor efficacy of an epithelial growth factor Receptor kinase inhibitor (EGFR-KI) and Taxol.
- To evaluate a novel transgenic organ tumor model for drug testing.
Main Methods:
- Utilized a genetically engineered tumor model in immune-competent mice with transplanted epithelial cells.
- Administered varying doses of EGFR-KI orally and Taxol intravenously.
- Performed histopathological evaluation and analyzed tumor cell proliferation using anti-Ki67 antibodies via laser scanning cytometry.
Main Results:
- EGFR-KI demonstrated dose-dependent antitumor efficacy, with optimal effects observed between 38-75 mg/kg.
- A strong correlation was found between tumor behavior, histopathology, and cell proliferation.
- Taxol treatment did not significantly reduce tumor growth or cell proliferation in this model.
Conclusions:
- The transgenic organ model is a suitable system for testing drug candidates targeting specific pathways.
- This model, with its c-erbB2 overexpression, may offer greater predictive value for human clinical effects compared to conventional models.
- EGFR-KI shows promise as an effective therapeutic agent in this specific tumor model.
