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Targeted molecular therapy for oral cancer with epidermal growth factor receptor blockade: a preliminary report
Jeffrey N Myers1, F Christopher Holsinger, B Nebiyou Bekele
1Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston 77030-4009, USA. jmyers@mdanderson.org
Background:
Overexpression of epidermal growth factor receptor (EGF-R) is associated with increased malignant potential and correlates with poor clinical outcome in head and neck cancer. Therefore, inhibition of the EGF-R pathway provides an ideal target for molecular therapy. We examined in vitro and in vivo effects of PKI166, an orally administered EGF-R inhibitor, on 2 human squamous cell carcinoma of the oral cavity cell lines, Tu159 and MDA1986.
Study Design:
Basic science, laboratory investigation.
Results:
For Western blotting, Tu159 and MDA1986 cells were pretreated for 1 hour and then stimulated with EGF. The EGF-R-specific tyrosine kinase autophosphorylation was inhibited completely by PKI166 at all doses tested (1-10 micro g/mL). By means of a tetrazolium-based viable cell assay, PKI166 was shown to arrest the growth of Tu159 and MDA1986 cells. The inhibitory concentration (50%), calculated from regression lines on the linear portion of the growth inhibition graphs, was 0.18 micro M (R = 0.98) for Tu159 cells and 0.23 micro M (R = 0.97) for MDA1986 cells. Nude mice were inoculated subcutaneously with 1 x 10(6) Tu159 tumor cells and observed for 7 days. Next, daily doses of PKI166 (0, 10, or 50 mg/kg) were delivered by orogastric lavage for 28 days and the animals were observed for tumor growth. PKI166 significantly reduced tumor growth in mice treated for 1 month with oral PKI166 in a dose-dependent fashion.
Conclusions:
Targeted molecular therapy with EGF-R blockade arrests the growth of oral cancer in vitro and reduces its proliferation in an experimental xenograft animal model.
Insights
Targeted therapy with epidermal growth factor receptor (EGF-R) inhibitor PKI166 effectively reduced oral cancer cell growth in laboratory studies and animal models. This molecular therapy shows promise for treating head and neck cancers.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Epidermal growth factor receptor (EGF-R) overexpression is linked to poor outcomes in head and neck cancers.
- Targeting the EGF-R pathway offers a potential molecular therapy strategy.
- PKI166 is an orally administered inhibitor of EGF-R.
Purpose of the Study:
- To investigate the in vitro and in vivo effects of PKI166 on human oral squamous cell carcinoma.
- To evaluate PKI166's efficacy in inhibiting EGF-R signaling and cell proliferation.
Main Methods:
- In vitro studies using Tu159 and MDA1986 oral cancer cell lines.
- Western blotting to assess EGF-R autophosphorylation inhibition.
- Tetrazolium-based viable cell assays to determine growth inhibition.
- In vivo studies using a nude mouse xenograft model.
Main Results:
- PKI166 completely inhibited EGF-R tyrosine kinase autophosphorylation in a dose-dependent manner.
- PKI166 demonstrated significant growth inhibition of oral cancer cells in vitro (IC50 values of 0.18 µM and 0.23 µM).
- PKI166 significantly reduced tumor growth in a xenograft mouse model over 28 days.
Conclusions:
- Targeted molecular therapy using EGF-R blockade with PKI166 is effective.
- PKI166 arrests oral cancer cell growth in vitro.
- PKI166 reduces oral cancer proliferation in an experimental animal model.