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A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor, shows antimetastatic activity using a
Mitsuhiro Matsuo1, Hiroaki Sakurai, Ikuo Saiki
1Department of Pathogenic Biochemistry, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, Toyama 930-0194, Japan.
Abstract:
The epidermal growth factor receptor (EGFR) is highly expressed in many human tumors and provides a new target for anticancer drug development. EGFR-targeted agents have shown promising antitumor activity in preclinical and clinical trials. However, little is yet known about the effect of these new agents on tumor metastasis. Here, we investigate the effects of ZD1839 (Iressa), a selective EGFR tyrosine kinase inhibitor, on the metastatic properties of murine hepatocellular carcinoma CBO140C12. ZD1839 inhibited not only cell growth but also epidermal growth factor-induced chemotactic migration and production of active matrix metalloproteinase-9 in vitro. In mice, orthotopic implantation of a fragment of CBO140C12 tumor into the liver resulted in the formation of a solitary tumor nodule and intrahepatic metastasis. ZD1839, given p.o., inhibited growth of the implanted tumor and intrahepatic metastasis by approximately 50%. These results indicate that EGFR signaling plays an important role in tumor metastasis and that ZD1839 is effective at inhibiting intrahepatic metastasis.
Insights
ZD1839 (Iressa), an epidermal growth factor receptor (EGFR) inhibitor, effectively reduced hepatocellular carcinoma growth and intrahepatic metastasis in mice. This study highlights EGFR
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Epidermal growth factor receptor (EGFR) is highly expressed in numerous human tumors.
- EGFR-targeted therapies show promise in preclinical and clinical studies.
- The impact of EGFR inhibitors on tumor metastasis remains largely unexplored.
Purpose of the Study:
- To investigate the effects of ZD1839 (Iressa), a selective EGFR tyrosine kinase inhibitor, on the metastatic properties of murine hepatocellular carcinoma.
- To elucidate the role of EGFR signaling in tumor metastasis.
Main Methods:
- In vitro assays assessed cell growth, epidermal growth factor-induced chemotactic migration, and matrix metalloproteinase-9 activity.
- Orthotopic implantation of CBO140C12 hepatocellular carcinoma cells into mouse livers.
- Oral administration of ZD1839 to evaluate its effects on tumor growth and intrahepatic metastasis.
Main Results:
- ZD1839 inhibited hepatocellular carcinoma cell growth and epidermal growth factor-induced migration in vitro.
- ZD1839 reduced the production of active matrix metalloproteinase-9 in vitro.
- In vivo, ZD1839 significantly inhibited both primary tumor growth and intrahepatic metastasis by approximately 50%.
Conclusions:
- EGFR signaling is crucial for hepatocellular carcinoma metastasis.
- ZD1839 demonstrates significant efficacy in inhibiting intrahepatic metastasis.
- Targeting EGFR represents a viable strategy for combating tumor spread in hepatocellular carcinoma.
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