novel mechanism of action and power to target both cycling and low cycling cells in vitro has delivered flavopiridol an interesting choice for combination with traditional cytotoxic therapies. In these studies, flavopiridol is administered as an initial cytoreductive agent for 3 days, following which the remaining leukemic cells could be recruited in to the cell cycle and therefore be kinetically sensitized for cytotoxicity from the 72 hour continuous administration of cytarabine Crizotinib PF-2341066 beginning on day 6 and mitoxantrone on day 9 12, 13. In a recent phase II study of this regimen in 62 patients with poor risk AML, flavopiridol was straight cytotoxic, with 44% of patients experiencing 50% decrease in peripheral blasts by day 2 and 26-year experiencing 800-676 decrease in blasts by day 3. CRs were achieved in 75-foot of patients with recently diagnosed secondary AML and those with first relapse after short CR. Rates of CR were somewhat lower for individuals with refractory disease. Disease free survival for several CR patients was 40% at 24 months 13. These results have also been expanded to a different cohort of 45 patients with recently diagnosed, Cellular differentiation poor risk AML. Of those, 67% achieved 40% and CR underwent a myeloablative allogeneic bone marrow transplant in first CR, translating into long haul survival 14. Alternative dosing schedules of flavopiridol may also be being studied. A hybrid bolus infusion schedule of flavopiridol continues to be investigated in CLL with promising results. Within this approach, a pharmacologically modeled schedule of flavopiridol is administered, having a 30 minute bolus of around half of the total dose, followed by a 4 hr infusion of the remaining portion, in a effort to overcome the observed effects of avid binding of flavopiridol by human plasma proteins 15, 16. This Ivacaftor VX-770 cross agenda of flavopiridol government is currently being studied in a dose escalation, phase I trial of patients with primary refractory and relapsed AML. Correlative in vivo pharmacodynamic studies demonstrate flavopiridol induced suppression of target genes, including cyclin D1, VEGF, E2F1, STAT 3, MCL 1, and RNA polymerase II 17. Among these are histone deacetylase inhibitors, which allow for acetylation of histones with resultant conformational changes and transcription of genes that allow differentiation, development arrest, and/or apoptosis 18. Interestingly, HDIs up regulate the expression of MCL 1, an antiapoptotic member of the bcl 2 family 19, and p21, a cyclin dependent kinase inhibitor 20, which together can limit the efficacy of these agents. Therefore, remedies that could down regulate expression MCL p21 and 1, such as for instance flavopiridol, may be synergistically efficacious in combination with HDIs.