gw2974 and Mouth-Neoplasms

Oral cancer is a common neoplasm worldwide with tobacco and alcohol being the major etiological factors contributing to its pathogenesis. Epidermal growth factor receptor (EGFR) and ErbB2 are known to be involved in the development of oral cancer with the former up-regulated in up to 90% human cases. The goal of this study was to evaluate the chemopreventive effects of a dual inhibitor of EGFR and ErbB2 tyrosine kinases, GW2974, in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch model. A short-term experiment (3-week topical DMBA followed by 1-week topical GW2974) was conducted to examine the effects of GW2974 on aberrant arachidonic acid (AA) metabolism and cell proliferation in the hamster oral epithelium. Topical application of 0.1 ml GW2974 (160 microM, three times a week) significantly reduced the levels of prostaglandin E2 (PGE2), leukotriene B4 (LTB4), 5-, 12-, 15-hydroxyeicosatetraenoic acid (HETE), and cell proliferation (BrdU-labeling index). In a long-term post-initiation experiment (6-week topical DMBA followed by 18-week topical GW2974), GW2974 (4 mM and 8 mM) significantly inhibited the incidence, number and size of visible tumors. Under microscope, the numbers of oral lesions (hyperplasia, dysplasia, carcinoma) and the incidence of squamous cell carcinoma (SCC) were also significantly suppressed by GW2974. In summary, our study indicated that dual inhibition of EGFR and ErbB2 tyrosine kinases by GW2974 was effective in preventing oral carcinogenesis in DMBA-induced hamster cheek pouch model. GW2974 exerted its chemopreventive effects in part by suppressing aberrant AA metabolism.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Arachidonate 5-Lipoxygenase; Carcinogens; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Cheek; Cricetinae; Dinoprostone; ErbB Receptors; Humans; Male; Mouth Mucosa; Mouth Neoplasms; Quinazolines; Receptor, ErbB-2

To evaluate the inhibiting effects of GW2974, a tyrosine kinase inhibitors, on dimethyl-benzanthracene (DMBA)-induced Syrian golden hamster buccal pouch carcinogenesis.. Ninety hamsters were painted with 0.5% DMBA in the left buccal pouches three times a week for 6 weeks, which were then divided into 3 groups: low-concentration, high-concentration and positive control groups. Positive control group received no further treatment. Ten hamsters served as negative control. The two treated groups were topically painted with GW2974 (4 mmol/L) and GW2974 (8 mmol/L) three times a week, respectively. Tissue samples of the left cheek pouch were obtained at 24 th week. The average number, average volume and burden of tumor, incidence of tumor and the pathological changes of each group were recorded.. After GW2974 (4 mmol/L and 8 mmol/L) was applied topically, tumor incidence decreased from 80.0% (24/30) to 43.3% (13/30, P < 0.01) and 36.7% (11/30, P < 0.01) respectively, the average number of tumors decreased from 1.00 +/- 0.87 to 0.47 +/- 0.82 (P < 0.05) and 0.37 +/- 0.62 (P < 0.05), the average volume and burden of tumors also declined, tumor incidence decreased from 70.0% (21/30) to 40.0% (12/30, P < 0.05) and 33.3% (10/30, P < 0.01), the number of tumors declined from 1.83 +/- 1.91 to 0.67 +/- 0.99 (P < 0.05) and 0.43 +/- 0.68 (P < 0.01).. Topical application of GW2974 could significantly inhibit hamster buccal pouch carcinogenesis, which suggests that GW2974 may have a major impact in chemoprevention and treatment of oral cancer.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinoma, Squamous Cell; Cricetinae; Disease Models, Animal; Male; Mouth Neoplasms; Protein-Tyrosine Kinases; Quinazolines