gw2974 and Carcinoma

Prostate cancer is one of the most frequently diagnosed cancer in men. Treatment by radical prostatectomy, radiotherapy and anti-androgen drugs is successful in patients with localized cancer. However, prolonged androgen deprivation often leads to hormone refractory condition, associated with disease relapse. ErbB1 and ErbB2 activity has been correlated with androgen-independence. We determined the effects of GW2974, a dual inhibitor of ErbB-1 and ErbB-2 tyrosine kinase activity, on growth, NSE, chromogranin A and osteopontin cytosol content in the androgen-independent prostate cancer cell line PC-3. We found that PC-3 cell growth was inhibited by GW2974, whereas NSE and chromogranin A cell contents were stimulated and osteopontin cytosol level was not affected. The present data may have clinical implications for the treatment of advanced prostate cancer.

Topics: Androgens; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Carcinoma; Carrier Proteins; Cell Line, Tumor; Cell Proliferation; Chromogranin A; Cytosol; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Male; Osteopontin; Prostatic Neoplasms; Quinazolines; Receptor, ErbB-2

Biliary tract cancer (BTC) is the second most common primary hepatobiliary cancer after hepatocellular cancer. At the time of diagnosis, most BTC are at an advanced stage and are unresectable. There is presently no effective curative treatment of the advanced disease nor is there any effective clinical therapy that will prevent the development of BTC. All of these factors render gallbladder cancer nearly incurable with a poor survival rate. The aim of our study was to provide a better understanding of the mechanisms involved in the development of gallbladder carcinoma as the advancement of more effective treatment options would significantly improve prognosis. In the present study, we examined the effect of gefitinib, a selective epidermal growth factor receptor/tyrosine kinase inhibitor (EGFR/TKI), on the development of gallbladder carcinoma in BK5.erbB2 mice. In addition, we examined the effect of another quinazoline derivative, GW2974, which is able to block the activation of both the EGFR and erbB2, in this model. Animals were treated with either 400 ppm gefitinib or 200 ppm GW2974 as a supplement in the diet using either a chemopreventive or therapeutic protocol. The results show that both compounds were potent chemopreventive and therapeutic agents in this mouse model of human BTC. The results also suggest that activation of the EGFR plays an important role in development of BTC in this model and that targeting both the EGFR and erbB2 may be an effective strategy for treatment of this disease.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents; Blotting, Western; Body Weight; Carcinoma; Cell Line, Tumor; Disease Models, Animal; Enzyme Inhibitors; ErbB Receptors; Gallbladder; Gallbladder Neoplasms; Gefitinib; Humans; In Situ Nick-End Labeling; MAP Kinase Signaling System; Mice; Mice, Transgenic; Microscopy, Fluorescence; Neoplasms, Experimental; Phosphorylation; Protein-Tyrosine Kinases; Quinazolines; Receptor, ErbB-2; Tolonium Chloride