Background: Arsenic Trioxide (ATO) is effective in about 20% of patients with myelodysplasia (MDS); itsmechanisms of action have already been evaluated in vitro, but the in vivo activity is still notfully understood. Since ATO induces apoptosis in in vitro models, we compared theexpression of 93 apoptotic genes in patients' bone marrow before and after ATO treatment.For this analysis, we selected 12 patients affected by MDS who received ATO incombination with Ascorbic Acid in the context of the Italian clinical trial NCT00803530,EudracT Number 2005-001321-28. Methods: Real-time PCR quantitative assays for genes involved in apoptosis were performed usingTaqMan(R) Assays in 384-Well Microfluidic Cards "TaqMan(R) Human Apoptosis Array".Quantitative RT-PCR for expression of EVI1 and WT1 genes was also performed. Geneexpression values (Ct) were normalized to the median expression of 3 housekeeping genespresent in the card (18S, ACTB and GAPDH). Results: ATO treatment induced up-regulation of some pro-apoptotic genes, such as HRK, BAK1,CASPASE-5, BAD, TNFRSF1A, and BCL2L14 and down-regulation of ICEBERG. In themajority of cases with stable disease, apoptotic gene expression profile did not change,whereas in cases with advanced MDS more frequently pro-apoptotic genes were upregulated.Two patients achieved a major response: in the patient with refractory anemia thetreatment down-regulated 69% of the pro-apoptotic genes, whereas 91% of the pro-apoptoticgenes were up-regulated in the patient affected by refractory anemia with excess of blasts-1.Responsive patients showed a higher induction of BAD than those with stable disease.Finally, WT1 gene expression was down-regulated by the treatment in responsive cases. Conclusions: These results represent the basis for a possible association of ATO with other biologicalcompounds able to modify the apoptotic pathways, such as inhibitors of the BCL2 family.
via Journal of Hematology & Oncology
via Journal of Hematology & Oncology
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