| Autor: |
Karnes, William E., Weller*, Shaun G., Adjei*, Philip N., Kottke‡, Timothy J., Glenn*, Kahlil S., Gores*, Gregory J., Kaufmann‡, Scott H. |
| Zdroj: |
Gastroenterology; May 1998, Vol. 114 Issue: 5 p930-939, 10p |
| Abstrakt: |
Background & Aims:The epidermal growth factor receptor (EGFR) is under investigation as a therapeutic target for cancers. Colon cancer cell lines are variably dependent on autocrine stimulation of EGFR. We therefore examined the effects of a selective EGFR tyrosine kinase inhibitor, PD 153035, on proliferation and survival of five colon cancer cell lines whose autonomous proliferation is either EGFR ligand dependent or EGFR ligand independent. Methods:Effects of inhibitors were screened by MTS growth assays, [3H]thymidine incorporation, terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling assay, fluorescence microscopy, immunoblotting, and in vitro protease assays. Results:PD 153035 caused dose-dependent cytostasis (200 nmol/L to 1 μmol/L) and apoptosis (10 μmol/L) in ligand-dependent cell lines and caused variable apoptosis (10 μmol/L) but no cytostasis in ligand-independent cell lines. Apoptosis induced by 10 μmol/L PD 153035 was not associated with induction of p53 protein expression but was accompanied by activation of caspases that cleave poly(ADP-ribose) polymerase, lamin B1, and Bcl-2. Inhibition of caspase 3–like protease activity by DEVD-fluoromethylketone significantly delayed the onset of PD 153035–induced apoptosis. Conclusions:The EGFR tyrosine kinase inhibitor PD 153035 induces cytostasis and caspase-dependent apoptosis in EGFR ligand-dependent colon cancer cell lines. These observations encourage further investigation of EGFR tyrosine kinase inhibitors for treatment of colorectal neoplasms. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
