This information will be instrumental in identifying the repertoire of HCC spec

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This information will be instrumental in identifying the repertoire of HCC spec

Post  jy9202 on Fri Nov 20, 2015 4:38 am

Figure 6B demonstrates that from day 46 to day 59, the per centage of leukemia cells in the PHA 739358 treated group increased from about 10% to 40%, compared to the control group in which an increase from 55% to 70% was measured. Consistent with the percentage of leukemia cells observed in peripheral blood, the mice in the control group died rapidly, [You must be registered and logged in to see this link.] with a median survival time of 59 days, while the mice in the PHA 739358 treated group showed a distinctly prolonged survival time. Interestingly, splenomegaly of mice was less pronounced in the PHA 739358 treated group than in the vehicle treated group. Treatment with PHA 739358 appeared to be well tolerated, since there were no significant differences in weight loss or gain or changes in physical appearance between the two groups.

Discussion The current study tested the use of PHA 739358 for the treatment of Ph positive ALL in vitro and in vivo. Since PHA 739358 has dual activity against both BcrAbl [You must be registered and logged in to see this link.] and Aurora kinases, one could expect that the inhibition of Ph positive ALL would be more profound than that of Ph negative ALL. However, we could not detect an increased effect on the Ph positive samples, and Ph posi tive samples with or without the T315I mutation did not differ significantly in sensitivity. Our results with the mutants agree with Gontarewicz et al. who reported that PHA 739358 was effective against imatinib resistant Bcr Abl mutants including those with the T315I mutation in human and mouse leukemia cell lines as well as in CD34 cells from an imatinib resistant CML patient.

We did notice that [You must be registered and logged in to see this link.] for some samples, dose escalation did not result in a proportionally larger response. This effect was quite marked in, for example, Pt2. Although treatment with 500 nM PHA 739358 caused a drop in viability to around 40% in 3 days, a 10 fold increased dose of 5 uM did not increase the percentage of apop totic cells or decrease the viability. Similarly, a 100 fold difference of drug exposure of UCSF02 did not cause a corresponding increased loss in viability. The lack of dose proportionality might be due to satur ation of the mechanism at low concentrations. Indeed, data from the colony formation assays show that a sig nificant part of the effects of PHA 739358 are due to its growth inhibitory activity, which is seen at a concentra tion as low as 10 nM.

In other cancers, deletion or mutation of p53 has been shown to result in resistance to the induction of apop tosis. We therefore examined whether any of the ALL samples contained p53 mutations using RTPCR but none were detected. Only US6 showed lack of an RTPCR product, suggesting bi allelic loss of p53. These cells reacted to the drug by accumulation of cells with a DNA content of 4N but the amount of cells with a sub G1 DNA content was less than BLQ1, which is wild type for p53. Interestingly, in hepatocellular carcinoma cell lines, Benten et al also found that PHA 739358 exhibits activity against both p53 wild type and mutated cancers. In initial studies using 8093 murine BcrAbl transgenic ALL cells transplanted into C57Bl recipients, we found that, compared to control mice, mice that had been trea ted with 30 mgkgbid i.


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