DMXAA ASA404 growth delay Gerung after a combined treatment more than the sum

PS treatment shown in Figure 6B. For the MiaPaCa2 xenograft model, the time required for tumors of cro 172-1500 mm 3 from 35.8 to 1.4 days for Mice, which increased to 44.4 DMXAA ASA404 1.8 days with vehicle Be ht for AZD6244-treated M Mice. Treatment with radiation alone increased ht The necessary time to 1500 to 41.8 mm3 2.3 days to reach. However, mice in M, Who again U combination AZD6244 IR time for tumors of up to 1500 mm 3 increased Ht grow from 1.2 to 54.8 days. The delay Wrestled were absolute growth of 8.5 to 50 mg / kg and 5.9 AZD6244 alone for radiotherapy alone, was the delay Gerung of tumor growth by AZD6244 IR treatment induced 18.9. Thus, the growth delay Gerung after a combined treatment more than the sum of the growth of individual delay Wrestled treatments caused.
The reinforcing Rkungsfaktor for the addition of dose AZD6244 in MiaPaCa2 xenograft model was 2.3. These data show that AZD6244 a significant increase in cytotoxicity t induced by radiation in vitro clonogenic assays and in tumor growth delay Storage at the A549 and MiaPaCa2 xenografts. These effects lead to a decrease in G2 checkpoint activation and increased Hten fully understand the signaling events, which after irradiation and development of inhibitors of these pathways new avenues of research on GE Occur Opens correspond use of targeted therapies such as radiation sensitizers. Signaling through the Ras-Raf-MEK-ERK is known that radiation in resonance and radiation resistance important. Thus, inhibition of this pathway an attractive means for tumor cells to sensitize to ionizing radiation.
To test the availability of AZD6244 is a specific inhibitor of MEK 1/2, an M Possibility, this hypothesis using a clinically relevant molecule. The point here pr Sentierten data indicate that AZD6244 radiosensitivity of tumor cells in vitro and in vivo improved. Treatment of A549, MiaPaCa2 and DU145 cell lines with AZD6244 led to an increase Increase the radiation sensitivity. The treatment of these cell lines with AZD6244 with the same concentration used in clonogenic assays was entered Born inhibition of ERK1 / 2 activation, a specific goal of AZD6244 and a downstream signaling event after irradiation. Most cell lines sensitive to AZD6244 as a single agent has been found that possess activating mutations in KRAS BRAF or RNA, or genes.
Both cell lines mutated KRAS, have been tested A549 and MiaPaCa2 showed a gr Eres awareness of radiation, when treated with AZD6244 as compared to wild-type RAS line, DU145. Expressing cell line DU145 and secrete EGFR EGF, which acts via a known method for stimulating the autocrine growth factors. The inhibition of EGFR has been shown that radiation sensitivity confinement in a variety of cell lines Improve Lich DU145 cell line. It is m Possible that the inhibition of this autocrine pathway with AZD6244 treatment, contributed to the observed increase in radiation sensitivity. The finding that both lines with KRAS mutations were sensitized preferred, hypothesis generation than three lines were tested. Further work is required, NaH in order to kl Whether cell lines with mutations in KRAS have a gr Eres awareness of radiotherapy with AZD6244 as compared to a few lines of wild-type RAS. This information is h Tten important implications for the clinical potential of AZD6244 as a radiation itself

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