Values are the mean standard sellectchem error of the Inhibitors,Modulators,Libraries mean. One way ANOVA p 0. 0001. p 0. Inhibitors,Modulators,Libraries 01 p 0. 001. Intracellular cAMP concentrations fol lowing treatment with SC236 or L 161 982 for 30 mins. The chart shows mean values SEM for n 3. One way ANOVA p 0. 01, p values shown are for Bonferroni multiple comparisons test between selected groups. fold, p 0. 04. Expression of the other cell cycle regula tion genes remained unchanged. Similar induction in p21WAF1CIP1 expression was observed with PD153035, an EGFR tyrosine kinase inhibitor, an effect not seen with the PI 3 kinase inhibitor wortmannin, suggest ing transactivation of EGFR by EP4 as the likely mecha nism for the induction of p21WAF1CIP1.

Relationship between EGFR and PGE2 in regulating of cell proliferation EGFR transactivation appears important in PGE2 signal ling and our results suggested a role in regulation of cell cycle progression genes Inhibitors,Modulators,Libraries and thus proliferation. PGE2 mediates EGFR activation by the release of EGFR ligands. Amphiregulin is known to be the most abundant Expression of p21WAF1CIP1 in HT 29 Cells is regulated by EGFR trans activation through the EP4 receptor EGFR ligand in HCA7 cells, which exhibit PGE2 dependent proliferation and therefore constitute an excel lent in vitro model to examining interplay between pros taglandins and EGFR. The effect on HCA7 cell proliferation of a neutralising antibody to AR both alone and in combination with SC 236 was evaluated. Effects of SC 236 on cell pro liferation were again evident. At low concentration the AR neutralizing antibody had no effect, however at higher concentrations a small effect on cell proliferation was noted.

The effect of com bined treatment with COX 2 inhibitor and ARab was greater than that of either ARab or SC 236 alone, resulting in a greater than 50% reduction Inhibitors,Modulators,Libraries in proliferation relative to control. Relationship between expression Inhibitors,Modulators,Libraries of COX 2 and amphiregulin in CRC The relationship between COX 2 and AR expression in human CRC was next examined. The expression of amphiregulin transcript was quantified in 10 tumournormal pairs by qRT PCR and correlated with expression of COX 2 in the same samples. AR expression was greater in tumour relative to normal in 7 of 10 patients. A non significant positive correlation was observed between the tumournormal differences for COX 2 and AR in the samples assayed. Amphiregulin and COX 2 dependent cell growth in colon Amphiregulin and COX 2 dependent cell growth in colon cancer cells. Bar chart shows the effect on cell pro liferation of a neutralising antibody to amphiregulin, moreover a COX 2 inhibi tor or a combination of both for 24 hours. Values shown are the Mean SEM for n 5. One way ANOVA p 0. 0001, p values shown are for Bonfer roni multiple comparisons test between selected groups.