Cyclindependent Kinase Inhibitors

Multiple cyclin-dependent kinases (CDKs) including, CDK1, CDK2, CDK4/6, and CDK7, are targeted by the semi-synthetic flavone, flavopiridol (L86-8275, HMR 1275; National Cancer Institute, Bethesda, Maryland, U.S.A.) (49). Co-treatment with imatinib and flavopiridol led to increased mitochondrial damage, activation of caspases and apoptosis in CML cell lines but not in leukemia cell lines that did not express Bcr-Abl (49). In addition, this drug combination effectively induced apoptosis in an imatinib-resistant CML cell line that overexpressed Bcr-Abl (49). As mentioned earlier, synergistic induction of apoptosis has been reported for the combination of flavopiridol and the proteasome inhibitor, bortezomib, in imatinib-sensitive and resistant CML cell lines (48). Unlike some of the other therapeutic agents previously discussed, flavopiridol has only recently been recognized as a potential treatment for CML. A phase I trial to identify appropriate dose combinations of imatinib and flavopiridol was conducted in 2005 in 21 patients with Bcr-Abl-positive hematologic malignancies (50). This combination was found to be tolerable and was responsible for four objective responses, including two complete hematologic remissions (50). Further clinical trials will be required to establish the efficacy of drug combinations containing flavopiridol.

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