Clearly, we must go beyond a simple one gene one disorder concept and try to co

We hypothesised that a therapeutic window might exist for dormant map キナーゼ 阻害剤 cancer cells because of the addiction of malignant cells to survival gene expression, Results from clinical trials with roscovitine and flavopiridol including a trial incorp orating flavopiridol in combination chemotherapy of AML have shown some efficacy at sub toxic doses. TG02 at tolerated doses induced lasting complete remis sions in an AML xenograft model and at the time of writing, is in Phase 1 trials for refractory and relapsed leukaemias. We show that the specific transcriptional RP2 inhibitor DRB as well as TG02, roscovitine and flavopiridol down regulate RNA Polymerase II activation and RNA synthesis in both unmanipulated and dormancy enriched cells.<br><br> We have not attempted to pick out specific targets of RP2 down regulation, as these are multitudinous, Functionally they tend to be genes in volved in rapid cellular responses, such as apoptosis reg ulators, mitosis regulators and genes involved in signalling Linifanib 分子量 pathways such as several NFκB target genes, We have shown that apoptosis is induced by the spe cific RP2 inhibitor DRB and by flavopiridol and TG02, Roscovitine appears to work mainly by growth inhibition or a non apoptotic mechanism of death. It is noteworthy in this respect that gene expres sion profiling of agents inhibiting transcriptional CDKs found that DRB and flavopiridol had similar broad activ ity, whereas roscovitine had a narrower range of activity, Moreover, in our hands, micromolar concentrations of roscovitine were found to reduce viable cell concen tration in only 5 12 leukaemia samples studied in vitro in contrast to a robust response to TG02 at 100 nM, To further validate our results indicating that RP2 in hibitors target dormancy enriched KG1a cells, we sought agreement for our findings in primary material.<br><br> In con trast to cell lines, primary AML samples are enriched for cells in G0 of the cell cycle, We examined the extent of apoptosis induced by RP2 inhibitors in dormant and proliferative compartments of primary cells. As Annexin V is a highly sensitive marker for early apoptosis in LY3009104 dissolve solubility pri mary AML cells, we looked for a cell surface dormancy marker that could be used in conjunction with Annexin V to measure apoptosis in dormant compared to prolif erating cells.<br><br> CD71 is absent in un stimulated peripheral blood lymphocytes, in some cancer stem cells and in long term culture initiating cells from normal bone marrow, Analysis of patient samples co labelled with CD71 and Ki 67 indicated that CD71 is not expressed in dormant AML blasts, Co labelling of cells with CD71 and Annexin V clearly indicated the contrast between the high proportion of CD71neg apoptotic cells following treatment with DRB, flavopiridol or TG02 and the high CD71 expression in etoposide treated apoptotic cells. Even compensating for the plasma protein binding of the drug, the concentra tion of TG02 used in this experiment is readily achiev able in vivo in both animals and humans, Conclusion In conclusion, we have shown that RP2 inhibitors effect ively target both KG1a cells enriched for dormancy by mTOR inhibition and CD71neg primary leukaemia pa tient samples thus providing grounds for suggesting that transcriptional RP2 inhibitors may be a useful class of agent for targeting dormant cells thought to contribute to relapses in leukaemia.

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