P2X4 expression is robust in Western blot analysis and no difference
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P2X4 expression is robust in Western blot analysis and no difference
Cellular proliferation in primary samples has been confirmed previously using Tdr uptake with pHH3 expression correlating extremely well with the amount of prolifera tion. Mean basal pHH3 expression in the primary samples was 3. 01% of total cells. We have previously reported that Ivacaftor 分子量 basal pHH3 expres sion in our primary samples shows significant correla tion with aurora B mRNA levels. pHH3 expression was measured in 37 primary samples after 1 hrs treatment with 300 nM barasertib hQPA. IC50 was achieved in all but 2 samples with a mean down regulation of 78%. Of the primary samples tested 9/37 were positive for Pgp and 9/35 positive for BCRP. Mean MRK 16 test/control mean fluorescence intensity in the primary samples was 1. 13. Mean CSA modulation ratio in the primary samples was 1. 74.<br><br> Five samples co expressed Pgp and BCRP such that we found a significant correlation between Pgp and BCRP expres sion in our LDE 225 primary samples. The percentage of Pgp and BCRP positive samples and the co expression correla tion agrees with previously published data. Pgp positive samples were significantly less sen sitive to barasertib hQPA induced pHH3 inhibition than samples was noted. Whereas the transporter expressing cell lines were insensitive to down regulation of pHH3 at concentrations of up to 1000 nM barasertib hQPA even after 24 hours, IC50 pHH3 inhibition was achieved in 94. 6% of primary samples at 300 nM barasertib hQPA for one hour. Discussion The success of agents such as imatinib in the treatment of chronic myelogenous leukaemia has lead to an increase in confidence that small molecule inhibitors of specific kinases may prove to be highly effective anticancer agents.<br><br> The aurora kinase family are essential for normal mitotic progression and have attracted great interest as potential new therapeutic targets. Overexpression of aur ora kinases have been reported in many tumour types and linked to a poor prognosis. The aurora B kinase specific inhibitor barasertib hQPA has shown LY2109761 cell in vivo in vitro tumouricidal activity against a panel of tumour cell lines and xenograft models including those of AML origin. Our group have recently reported that the FLT3 ITD mutation is a sec ondary target for barasertib hQPA and that primary AML samples with an ITD mutation in the FLT3 gene are parti cularly sensitive to the drug.<br><br> The FLT3 gene is one of the most commonly mutated genes in AML with the FLT3 ITD mutation appearing in roughly 24% of cases Pgp negative samples. BCRP positive pri mary samples were also significantly less sensitive to barasertib hQPA induced pHH3 inhibition compared to BCRP negative samples. How ever, a sharp distinction between cell lines and primary and being associated with a poor prognosis. Bara sertib hQPA is therefore of potential use as a future treat ment in AML. Intrinsic MDR or treatment induced MDR has histori cally been one of the major obstacles to the effective treatment of patients with AML. Elevated expression of the MDR1 gene coding for the drug efflux pump Pgp is one of the best characterized resistance mechanisms in AML with high expression in elderly patients particu larly associated with worse complete remission rates.
jy9202- Количество сообщений : 532
Дата регистрации : 2013-12-16
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