CHEMOTHERAPY

  • Claxton, David (PI)
  • Andreeff, Michael (PI)
  • DEISSEROTH, ALBERT (PI)
  • ESTEY, ELIHU (PI)
  • CHAMPLIN, RICHARD (PI)
  • Plunkett, William (PI)
  • Andreeff, Michael (PI)
  • BENEDICT, WILLIAM (PI)
  • REED, JOHN (PI)
  • KORNBLAU, STEVEN (PI)
  • LIANG, JAN (PI)
  • SICILIANO, MICHAEL (PI)
  • READING, CHRISTOPHER (PI)
  • THALL, PETER (PI)
  • ESTEY, ELIHU (PI)
  • CHAMPLIN, RICHARD (PI)
  • Plunkett, William (PI)
  • Nagarajan, Lalitha (PI)
  • BENEDICT, WILLIAM (PI)
  • REED, JOHN (PI)
  • KORNBLAU, STEVEN (PI)
  • LIANG, JAN (PI)
  • SICILIANO, MICHAEL (PI)
  • READING, CHRISTOPHER (PI)
  • THALL, PETER (PI)
  • ESTEY, ELIHU (PI)
  • CHAMPLIN, RICHARD (PI)
  • KORNBLAU, STEVEN (PI)
  • CROCE, CARLO (PI)
  • BERRY, DONALD (PI)
  • THOMAS, MATTIE (PI)
  • Andreeff, Michael (PI)
  • REED, JOHN (PI)
  • CROCE, CARLO (PI)
  • ESTEY, ELIHU (PI)
  • CHAMPLIN, RICHARD (PI)
  • KORNBLAU, STEVEN (PI)
  • BERRY, DONALD (PI)
  • THOMAS, MATTIE (PI)
  • Andreeff, Michael (PI)
  • Andreeff, Michael (PI)
  • Andreeff, Michael (PI)
  • Andreeff, Michael (PI)
  • Andreeff, Michael (PI)
  • Andreeff, Michael (PI)
  • Andreeff, Michael (PI)

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date1/1/018/31/15

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