This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This study proposes that simultaneously interrupting cell cycle and survival signaling pathways will exert synergistic antileukemic effects in Bcr/abl+ malignancies and that this strategy may be effective in at least a subset of STI571-resistant cells through Bcr/Abl amplification or increased protein expression. Flavopiridol is a semisynthetic flavone, derived from the flavonoid rohitukine, which acts as potent inhibitor of multiple cyclin-dependent kinases (CDKs). Flavopiridol has been shown to exhibit anti-angiogenic activity and is the first of the pharmacologic CDK inhibitors to enter clinical trials in humans. As anticipated from its mechanism of action, flavopiridol is a potent inhibitor of cell cycle traverse, triggering cell cycle arrest in G1 as well as in G2M. Flavopiridol is also an effective inducer of apoptosis, particularly in malignant hematopoietic cells. Recently, flavopiridol has been shown to act as a transcriptional regulator as a consequence of its ability to inhibit the CDK9/TEFb complex. Several theoretical considerations support the concept that combining flavopiridol with imatinib may result in a significant potentiation of lethality in Bcr/Abl+ cells. First, flavopiridol is broadly active against human leukemia cells, and induces apoptosis in such cells at sub-micromolar concentrations. Second, previous studies indicate that simultaneous disruption of a survival signaling pathway and disruption of a cell cycle regulatory pathway results in a pronounced increase in cell death. More recent studies indicate that MEK inhibitors interact synergistically with imatinib in Bcr/Abl+ cells. Thus, CDK inhibition by flavopiridol may, when combined with Bcr/Abl disruption (e.g., imatinib) may lead to synergistic antileukemic effects through a similar mechanism. In this regard, recent studies indicate that simultaneous administration of flavopiridol with imatinib in Bcr/Abl+ cells leads to a marked increase in mitochondrial damage, casapase activation, and apoptosis. Such events were associated with multiple perturbations in signaling/cell cycle regulatory pathways, including down-regulation of Mcl-1, cyclin D1, phospho-Creb, cleavage of pRb, and activation of the stress-related JNK kinase. Significantly, synergistic interactions between flavopiridol and imatinib were observed in imatinib-resistant Bcr/Abl+ cells exhibiting increased Bcr/Abl expression. Such findings raise the possibility that combining flavopiridol with imatinib may be effective against at least the subset of Bcr/Abl+ cells that are resistant to imatinib through Bcr/Abl amplification or increased protein expression. Patients are enrolled into one of two groups based upon the peripheral blood and bone marrow blast count at the time of enrollment. Study drugs will be administered in the appropriate dosage and patients will be monitored. Pathology specimens, medical records, data, blood specimens for pharmacokinetic/pharmacodynamic (PK/PD) analysis will be obtained. All tests/procedures, except the PK/PD would be performed if patients were treated off-study.
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