I. RATIONALE: Our program in newly-diagnosed AML has focused on the development of agents to selectively increase the susceptibility of clonogenic blasts to chemotherapy. This approach is based on the concept that increasing the rate of proliferation, specifically entry into S phase, of AML blasts can sensitizes the cells to the current mainstays of therapy (araC, idarubicin and fludarabine) which kill cells by programmed cell death (PCD) through apoptosis. We have demonstrated that the combination of G- CSF, fludarabine, and ara-C (FLAG) induces, for the first time, CR rates in excess of 50% in AML patients with abnormalities of chromosomes 5 and/or 7. Despite improved CR rates, remission durations, however, remain short in poor prognosis subsets of AML. These results suggest that cytokines such as G-CSF and other growth regulatory molecules, such as lysophosphatidic acid (LPA) could increase sensitively to the apoptotic action of chemotherapeutics. However, some cytokines could potentially interfere with the induction of PCD by chemotherapeutics. Since programmed cell death appears to be the final common mechanism by which DNA damaging agents, such as many chemotherapeutics, including those used in the therapy of AML, kill cells, cytokines and growth factors may exert a dual effect both increasing sensitivity to the actions of cytotoxic drugs by increasing cell proliferation and potentially protecting cells by inhibiting programmed cell death. II. HYPOTHESIS: That the effect of growth modulators on the outcome of AML therapy reflects the balance between increased sensitivity to drug induced PCD and protection from cell death. Thus shifting the balance towards PCD may improve patient responses. The goal of this application is to determine whether the balance between the potential dualistic effect of cytokines and growth factors on sensitization and inhibition of drug action determines the net response in patients comprising the various subsets of AML. In addition, we will determine in vitro, ex vivo, and by clinical response whether the dualistic effect of cytokines such as G-CSF and growth regulatory molecules such as LPA shift AML cells towards PCD and whether PCD can be further promoted through addition of all trans retinoic acid (ATRA) or rapamycin, both of which have been demonstrated to increased the sensitivity to chemotherapy-induced PCD. III.
SPECIFIC AIMS : 1. To determine whether randomization of addition of G-CSF to therapy with fludarabine + ara-C + idarubicin (FAI) in poor prognosis AML/MDS will affect cell proliferation, entry into S phase, PCD, expression of proteins involved in PCD, sensitivity to FAI, and response to therapy. 2. To determine whether randomization of addition of retinoids (all trans retinoic acid ATRA) added to FAI + G-CSF will affect cell proliferation, entry into S phase, PCD, expression of proteins involved in PCD, sensitivity to FAI, and response to therapy. 3. To determine whether increasing the production of lysophosphatidic acid (LPA) with lisofylline (LSF) in good prognosis AML patients receiving ara-C alters the balance between proliferation and PCD and whether this alteration will improve clinical outcome in these patients. 4. To determine whether rapamycin or IFN will enhance chemotherapy-induced PCD in AML cells by altering expression of proteins regulating PCD in in vitro model systems to determine whether these combinations should be assessed in clinical trials.
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