Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia

Byrd, John C.; Lin, Thomas S.; Dalton, James T.; Wu, Di; Phelps, Mitch A.; Fischer, Beth; Moran, Mollie E.; Blum, Kristie A.; Rovin, Brad H.; Brooker-McEldowney, Michelle; Broering, Sarah; Schaaf, Larry J.; Johnson, Amy J.; Lucas, David M.; Heerema, Nyla A.; Lozanski, Gerard; Young, Donn C.; Suarez, Jose-Ramon; Colevas, A. Dimitrios; Grever, Michael R.

doi:10.1182/blood-2006-05-020735

Cited by 363 publications

(316 citation statements)

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“…Flavopiridol was obtained from the National Cancer Institute and used at either 1.0 or 1.5 M as stated in the text, based on pharmacokinetic data from treated CLL patients. 2 Experiments conducted with both 1.0 and 1.5 M flavopiridol showed very similar results. In whole blood experiments, flavopiridol was used at 3.0 M due to its extensive binding to human plasma proteins.…”

Section: Cll Patient Samples and Cell Culturesupporting

confidence: 67%

“…Our group recently demonstrated significant clinical efficacy of flavopiridol in patients with refractory chronic lymphocytic leukemia (CLL) using a novel schedule of administration. 2 Approximately 50% of CLL patients who receive flavopiridol using this schedule exhibit biochemical signs of tumor lysis (elevated potassium and phosphate levels, reduced calcium levels) occurring as early as 4.5 hours after treatment initiation. In limited cases with highly elevated peripheral white blood cell counts, this tumor lysis can be severe enough to require dialysis.…”

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confidence: 99%

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Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia cells with impaired oxygen consumption and mobilization of intracellular calcium

Hussain

Lucas

Johnson

et al. 2008

Blood

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Effective administration of flavopiridol in advanced-stage chronic lymphocytic leukemia (CLL) is often associated with early biochemical evidence of tumor cell lysis. Previous work using other cell types showed that flavopiridol impacts mitochondria, and in CLL cells flavopiridol down-regulates the mitochondrial protein Mcl-1. We therefore investigated mitochondrial structure and function in flavopiridol-treated CLL patient cells and in the lymphoblastic cell line 697 using concentrations and times at which tumor lysis is observed in treated patients. Mitochondrial membrane depolarization was detected in flavopiridol-treated CLL cells by 6 hours, well before the onset of cell death. Flavopiridol-induced mitochondrial depolarization was not blocked by caspase inhibitors or by the calcium chelator EGTA, but was reduced by Bcl-2 overexpression. Intracellular calcium mobilization was noted at early time points using fluorescence microscopy. Furthermore, electron paramagnetic resonance oximetry showed a gradual but significant reduction in cellular oxygen consumption rate by 6 hours, corresponding with ultrastructural mitochondrial damage detected by electron microscopy. IntroductionFlavopiridol is a semisynthetic flavone (N-methylpiperidinyl chlorophenyl flavone) that is considered to act broadly as a cyclindependent kinase (CDK) inhibitor. 1 However, the in vivo mechanism of action of flavopiridol is not well understood, and may involve actions other than or inclusive of CDK inhibition. Our group recently demonstrated significant clinical efficacy of flavopiridol in patients with refractory chronic lymphocytic leukemia (CLL) using a novel schedule of administration. 2 Approximately 50% of CLL patients who receive flavopiridol using this schedule exhibit biochemical signs of tumor lysis (elevated potassium and phosphate levels, reduced calcium levels) occurring as early as 4.5 hours after treatment initiation. In limited cases with highly elevated peripheral white blood cell counts, this tumor lysis can be severe enough to require dialysis. This observation suggests that flavopiridol, when effectively administered, induces very rapid cell death that is atypical of classical apoptosis. However, more work is needed to understand this process and to better predict which patients may experience severe tumor lysis.Multiple previous studies in different cell types have incriminated mitochondrial mechanisms in flavopiridol-induced apoptosis, although conditions and time points under which this is noted vary widely and are often reported in combination with other agents. [3][4][5][6][7][8][9][10][11] Several reports showed that flavopiridol induces mitochondrial membrane disruption and release of cytochrome c in the U937 human monoblastic leukemia cell line and that these effects were potentiated by phorbol myristate acetate (PMA). 4,9,10 This process in U937 cells was noted to be partially caspase independent, as a general caspase inhibitor blocked flavopiridol-induced loss of mitochondrial membrane potential (⌬⌿ m ) but ...

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Section: Cll Patient Samples and Cell Culturesupporting

confidence: 67%

mentioning

confidence: 99%

Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia cells with impaired oxygen consumption and mobilization of intracellular calcium

Hussain

Lucas

Johnson

et al. 2008

Blood

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“…This provided a proof of action of flavopiridol as a transcriptional inhibitor because most primary CLL cells are not actively cycling and therefore do not require the cell cycle-regulating CDKs. An ongoing clinical trial of flavopiridol has recently reported promising activity in refractory CLL (11).…”

Section: Introductionmentioning

confidence: 99%

A Sequential Blockade Strategy for the Design of Combination Therapies to Overcome Oncogene Addiction in Chronic Myelogenous Leukemia

2006

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Some tumors are dependent on the continued activity of a single oncogene for maintenance of their malignant phenotype. The best-studied example is the Bcr-Abl fusion protein in chronic myelogenous leukemia (CML). Although the clinical success of the Abl kinase inhibitor imatinib against chronicphase CML emphasizes the importance of developing therapeutic strategies aimed at this target, resistance to imatinib poses a major problem for the ultimate success of CML therapy by this agent. We hypothesized a sequential blockade strategy that is designed to decrease the expression of the Bcr-Abl protein, with the goal of complementing the action of imatinib on kinase activity. In this study, flavopiridol, an inhibitor of transcription, homoharringtonine (HHT), a protein synthesis inhibitor, and imatinib were used singly and in combination against the Bcr-Abl-positive human CML cell line K562. Flavopiridol alone inhibited phosphorylation of the RNA polymerase II COOH-terminal domain, specifically reduced RNA polymerase II-directed mRNA synthesis, and decreased the Bcr-Abl transcript levels. HHT inhibited protein synthesis and reduced the Bcr-Abl protein level. Imatinib directly inhibited the kinase activity of Bcr-Abl. The combinations of flavopiridol and HHT and flavopiridol and imatinib synergistically decreased clonogenicity as evaluated by the median-effect method. Greater synergy was observed when HHT and imatinib were given sequentially compared with simultaneous administration. Imatinib-resistant Ba/F3 cells that were transfected to express the E255K and T315I mutations of Bcr-Abl were not cross-resistant to flavopiridol and HHT. These results provided a rationale for the combination of inhibitors of transcription and/or translation with specific kinase inhibitors. (Cancer Res 2006; 66(22): 10959-66)

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“…Each has been progressed against several indications in both solid and hematologic malignancies. Flavopiridol has shown clinical activity in chronic lymphocytic leukemia (26,27). SNS-032 is reported to be in phase I/II development in advanced breast cancer, melanoma, non-small cell lung cancer, and B-cell malignancies (28,29).…”

Section: Introductionmentioning

confidence: 99%

Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines

Squires¹,

Feltell²,

Wallis³

et al. 2009

Molecular Cancer Therapeutics

155

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Cyclin-dependent kinases (CDK), and their regulatory cyclin partners, play a central role in eukaryotic cell growth, division, and death. This key role in cell cycle progression, as well as their deregulation in several human cancers, makes them attractive therapeutic targets in oncology. A series of CDK inhibitors was developed using Astex's fragment-based medicinal chemistry approach, linked to high-throughput X-ray crystallography. A compound from this series, designated AT7519, is currently in early-phase clinical development. We describe here the biological characterization of AT7519, a potent inhibitor of several CDK family members. AT7519 showed potent antiproliferative activity (40-940 nmol/L) in a panel of human tumor cell lines, and the mechanism of action was shown here to be consistent with the inhibition of CDK1 and CDK2 in solid tumor cell lines. AT7519 caused cell cycle arrest followed by apoptosis in human tumor cells and inhibited tumor growth in human tumor xenograft models. Tumor regression was observed following twice daily dosing of AT7519 in the HCT116 and HT29 colon cancer xenograft models. We show that these biological effects are linked to inhibition of CDKs in vivo and that AT7519 induces tumor cell apoptosis in these xenograft models. AT7519 has an attractive biological profile for development as a clinical candidate, and the tolerability and efficacy in animal models compare favorably with other CDK inhibitors in clinical development. Studies described here formed the biological rationale for investigating the potential therapeutic benefit of AT7519 in cancer patients. [Mol Cancer Ther 2009;8(2):324 -32]

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Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia

Cited by 363 publications

References 35 publications

Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia cells with impaired oxygen consumption and mobilization of intracellular calcium

Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia cells with impaired oxygen consumption and mobilization of intracellular calcium

A Sequential Blockade Strategy for the Design of Combination Therapies to Overcome Oncogene Addiction in Chronic Myelogenous Leukemia

Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines

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