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MessagePosté le: Mer 20 Aoû - 10:53 (2014) Sujet du message: rufipogon and Xa27 gene sequence of O. officinalis ecotype Répondre en citant

 E6201 at forty mg kg in MM604 and SKMEL13 xenografts prevented tumour progression to the two weeks of drug remedy, with tumour growth recommencing following AP24534 943319-70-8 drug removal, while reduce doses of drug only attenuated, as opposed to prevented, tumour development in vivo. Only the highest dose of E6201 had any considerable inhibitory result on tumour growth in BL tumour bearing mice, when decrease drug doses had tiny or no effect on tumour pro gression. As this kind of our hypothesis was con firmed, with E6201 inhibiting xenograft tumour development in all four melanoma cell lines studied, and enhanced in vivo exercise observed for those cell lines that demon strated a cytocidal response in vitro.

E6201 and LY294002 Provided our former data suggesting that E6201 resistance is associated with mutation of PTEN and high levels of pAkt, we hypothesized that AT-406 cell in vivo in vitro combining E6201 with an in hibitor on the PI3K pathway in these cell lines may possibly re sult in either an additive or synergistic result. Additional file two, Figure S2 demonstrates that LY294002 efficiently inhibits PI3K by proof of diminished phosphorylated AKT protein ranges within the 4 PTEN mutant melanoma cell lines that usually express substantial amounts of pAKT. Furthermore, Added file 3, Figures S3 and Supplemental file 4, Figure S4 display the concentration impact curves for single agent LY294002 and E6201 respectively, the place both drugs had been added 24 hours following plating. The 6 melanoma cell lines examined displayed similar trends in E6201 sensitivity compared to our former experiments, with MM622, MM540, UACC903, and WM35 being by far the most delicate and UACC558 and UACC647 remaining significantly less sensitive.

Surprisingly, all cell lines showed equivalent sensitivity to LY294002, with IC50 ranging from eleven uM to 17 uM. This was sudden, as a single would predict MM540 and WM35 cells to become fairly resistant to PI3K inhibition given the lack of detectable levels of pAkt indicating akt1 阻害剤 no constitutive PI3K activation in these cell lines. A earlier research by Smalley and other people, on the other hand, reported a comparable sensitivity of WM35 cells to LY294002. The concentration response curves for E6201 and LY294002 combinations, normalized to a dimethyl sulf oxide management are given in Extra file four, Figure S4.

As differences in synergy may well exist at vary ent drug impact amounts, we graphed personal combin ation index values for LY294002 with increasing concentrations of E6201 for each cell line. As shown in Figure 5A, evaluating the individual com bination index for all combinations examined exposed that E6201 and LY294002 exhibit synergistic activity in all 6 melanoma cell lines, irrespective of E6201 sensitivity or PTEN or pAkt status. Interestingly, unique patterns of synergy were observed between the groups of cell lines examined. Even though the vast majority of the cell lines showed an in creasing combination index at larger concentrations of E6201, UACC647 and UACC558 cells showed a reducing mixture index or enhanced synergy with expanding concentrations of E6201. Notably, this pattern observed for UACC647 and UACC558 cells occurs inside of the context of higher pAkt and relative resistance to E6201, supporting the hypoth esis that administration of a PI3K inhibitor can sensitize E6201 resistant cells with substantial pAkt levels to E6201.


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MessagePosté le: Mer 20 Aoû - 10:53 (2014) Sujet du message: Publicité

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