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Adrian M. Senderowicz - One of the best experts on this subject based on the ideXlab platform.

  • Clinical Pharmacology of Flavopiridol Following a 72-Hour Continuous Infusion
    2016
    Co-Authors: Michelle A Rudek, Adrian M. Senderowicz, Kenneth S Bauer, Richard M Lush, Sherman F Stinson, Donna J Headlee, Susan G Arbuck, Michael C Cox, Anthony J Murgo, Edward A. Sausville
    Abstract:

    Flavopiridol is a novel flavone compound syntheticallyderived from a parent compound isolated from Dysoxy-lum binectariferum. In vitro studies have demonstrated that Flavopiridol inhibits cyclin-dependent kinase-1 (CDK1), the mediator of cell-cycle progression from G2 to M phase.1 Additional studies have also found that Flavopiridol is an inhibitor of CDK2, whose activity appears at the G1-S boundary.2 In addition, Flavopiridol has antiangiogenic activity and does not exhibit multidrug resistance in vitro.3 Based on this unique spectrum of in vitro activity, 4 Phase I studies and several Phase II clinical trials were initiated. We initiated a Phase I trial of Flavopiridol in patients with refractory solid tumors to determine the maximum tolerated dose and characterize the adverse effect profile.4 Secretory diarrhea was the dose-limiting toxicity when Flavopiridol was administered as a 72-hour continuous in-fusion every 2 weeks. Several different treatment and pro-phylactic regimens were tested to ameliorate the diarrhea. The best of these consisted of cholestyramine and lo-peramide. Nonetheless, Flavopiridol was well tolerated at doses of 50 mg/m2/d for 3 days without antidiarrheal pro-phylaxis and 78 mg/m2/d for 3 days with prophylaxis. Flavopiridol has entered widespread Phase II testing, with Phase III trials being planned. This article describes the clinical and laboratory studies conducted to characterize the clinical pharmacology of Flavopiridol from this trial. In addition, we explored the importance of enterohepatic re

  • Flavopiridol a novel cyclin dependent kinase inhibitor in clinical development
    Annals of Pharmacotherapy, 2002
    Co-Authors: Suoping Zhai, Edward A. Sausville, Adrian M. Senderowicz, William D Figg
    Abstract:

    OBJECTIVE:To review preclinical and clinical information on Flavopiridol, an inhibitor of cyclin-dependent kinases (CDKs), tested as an antitumor agent.DATA SOURCES:Primary and review articles were identified by MEDLINE search (1990–June 2001). Abstracts from recent meetings were also used as source materials.DATA EXTRACTION:Flavopiridol was reviewed with regard to its mechanisms, preclinical and clinical results, pharmacokinetics, and metabolism.DATA SYNTHESIS:Flavopiridol is an inhibitor of several CDKs and displays unique anticancer properties. In addition to direct CDK inhibition, Flavopiridol also exhibited other features such as inducing apoptosis in many cancer cell lines, decreasing cyclin D1 concentration, and inhibiting angiogenesis. Preclinical xenograft models showed significant antitumor activity for Flavopiridol. The regimen using 72-hour continuous infusion every 2 weeks has been most extensively applied in clinical trials, with a 1-hour infusion currently being explored to achieve higher p...

  • overexpression of the atp binding cassette half transporter abcg2 mxr bcrp abcp1 in Flavopiridol resistant human breast cancer cells
    Clinical Cancer Research, 2001
    Co-Authors: Robert W Robey, Adrian M. Senderowicz, Keisuke Miyake, Thomas Litman, Douglas D Ross, Wilma Y Medinaperez, Kenryu Nishiyama, Tyler Lahusen, Susan E Bates
    Abstract:

    We sought to characterize the interactions of Flavopiridol with members of the ATP-binding cassette (ABC) transporter family. Cells overexpressing multidrug resistance-1 (MDR-1) and multidrug resistance-associated protein (MRP) did not exhibit appreciable Flavopiridol resistance, whereas cell lines overexpressing the ABC half-transporter, ABCG2 (MXR/BCRP/ABCP1), were found to be resistant to Flavopiridol. Flavopiridol at a concentration of 10 μm was able to prevent MRP-mediated calcein efflux, whereas Pgp-mediated transport of rhodamine 123 was unaffected at Flavopiridol concentrations of up to 100 μm. To determine putative mechanisms of resistance to Flavopiridol, we exposed the human breast cancer cell line MCF-7 to incrementally increasing concentrations of Flavopiridol. The resulting resistant subline, MCF-7 FLV1000, is maintained in 1000 nm Flavopiridol and was found to be 24-fold resistant to Flavopiridol, as well as highly cross-resistant to mitoxantrone (675-fold), topotecan (423-fold), and SN-38 (950-fold), the active metabolite of irinotecan. Because this cross-resistance pattern is consistent with that reported for ABCG2-overexpressing cells, cytotoxicity studies were repeated in the presence of 5μ m of the ABCG2 inhibitor fumitremorgin C (FTC), and sensitivity of MCF-7 FLV1000 cells to Flavopiridol, mitoxantrone, SN-38, and topotecan was restored. Mitoxantrone efflux studies were performed, and high levels of FTC-reversible mitoxantrone efflux were found. Northern blot and PCR analysis revealed overexpression of the ABCG2 gene. Western blot confirmed overexpression of ABCG2; neither P-glycoprotein nor MRP overexpression was detected. These results suggest that ABCG2 plays a role in resistance to Flavopiridol.

  • Flavopiridol inhibits P-TEFb and blocks HIV-1 replication.
    Journal of Biological Chemistry, 2000
    Co-Authors: Shenghao Chao, David H Price, Koh Fujinaga, B. Matija Peterlin, Jon E. Marion, Edward A. Sausville, Adrian M. Senderowicz
    Abstract:

    Flavopiridol (L86-8275, HMR1275) is a cyclin-dependent kinase (Cdk) inhibitor that is in clinical trials as a cancer treatment because of its antiproliferative properties. We found that the flavonoid potently inhibited transcription by RNA polymerase II in vitro by blocking the transition into productive elongation, a step controlled by P-TEFb. The ability of P-TEFb to phosphorylate the carboxyl-terminal domain of the large subunit of RNA polymerase II was inhibited by Flavopiridol with a K(i) of 3 nm. Interestingly, the drug was not competitive with ATP. P-TEFb composed of Cdk9 and cyclin T1 is a required cellular cofactor for the human immunodeficiency virus (HIV-1) transactivator, Tat. Consistent with its ability to inhibit P-TEFb, Flavopiridol blocked Tat transactivation of the viral promoter in vitro. Furthermore, Flavopiridol blocked HIV-1 replication in both single-round and viral spread assays with an IC(50) of less than 10 nm.

  • induction of apoptosis and inhibition of c erbb 2 in breast cancer cells by Flavopiridol
    Clinical Cancer Research, 2000
    Co-Authors: Mahbubur Bhuiyan, Adrian M. Senderowicz, Samir Alhasan, Fazlul H Sarkar
    Abstract:

    Flavopiridol is a flavone that inhibits several cyclin-dependent kinases and exhibits potent growth-inhibitory activity against a number of human tumor cell lines, both in vitro and when grown as xenografts in mice. It is presently being investigated as a novel antineoplastic agent in the primary screen conducted by the Developmental Therapeutics Program, National Cancer Institute. Because breast cancer is the most common cancer and second leading cause of cancer-related deaths in women in the United States, we investigated whether Flavopiridol could be an effective agent against a series of isogenic breast cancer cell lines having different levels of erbB-2 expression and differential invasion and metastatic characteristics. Flavopiridol was found to inhibit the growth of MDA-MB-435 (parental) and 435.eB (stable transfectants) cells that were established by transfecting c-erb B-2 cDNA into MDA-MB-435. Induction of apoptosis was also observed in these cell lines when treated with Flavopiridol, as measured by DNA laddering, PARP, and CPP32 cleavages. We also found modest up-regulation of Bax and down-regulation of Bcl-2, but there was a significant down-regulation of c-erb B-2 in Flavopiridol-treated cells. Gelatin zymography showed that Flavopiridol inhibits the secretion of matrix metalloproteinase (MMP; MMPs 2 and 9) in the breast cancer cells and that the inhibition of c-erbB-2 and MMPs may be responsible for the inhibition of cell invasion observed in Flavopiridol-treated cells. Collectively, these molecular effects of Flavopiridol, however, were found to be independent of c-erbB-2 overexpression, suggesting that Flavopiridol may be effective in all breast cancer. From these results, we conclude that Flavopiridol inhibits the growth of MDA-MB-435 breast cancer cells, induces apoptosis, regulates the expression of genes, and inhibits invasion and, thus, may inhibit metastasis of breast cancer cells. These findings suggest that Flavopiridol may be an effective chemotherapeutic or preventive agent against breast cancer.

Judith E. Karp - One of the best experts on this subject based on the ideXlab platform.

  • exposure response analysis of alvocidib Flavopiridol treatment by bolus or hybrid administration in newly diagnosed or relapsed refractory acute leukemia patients
    Clinical Cancer Research, 2017
    Co-Authors: Carl Lacerte, Judith E. Karp, Vijay Ivaturi, Jogarao V S Gobburu, Jacqueline Greer, Austin Doyle, John J Wright, Michelle A Rudek
    Abstract:

    Purpose: To elucidate any differences in the exposure-response of alvocidib (Flavopiridol) given by 1-hour bolus or a hybrid schedule (30-minute bolus followed by a 4-hour infusion) using a Flavopiridol/cytosine arabinoside/mitoxantrone sequential protocol (FLAM) in patients with acute leukemia. The hybrid schedule was devised to be pharmacologically superior in chronic leukemia based on unbound exposure.Experimental Design: Data from 129 patients in three FLAM studies were used for pharmacokinetic/pharmacodynamic modeling. Newly diagnosed (62%) or relapsed/refractory (38%) patients were treated by bolus (43%) or hybrid schedule (57%). Total and unbound Flavopiridol concentrations were fit using nonlinear mixed-effect population pharmacokinetic methodologies. Exposure-response relationships using unbound Flavopiridol AUC were explored using recursive partitioning.Results: Flavopiridol pharmacokinetic parameters were estimated using a two-compartment model. No pharmacokinetic covariates were identified. Flavopiridol fraction unbound was 10.9% and not different between schedules. Partitioning found no association between dosing schedule and clinical response. Clinical response was associated with AUC ≥ 780 h*ng/mL for newly diagnosed patients and AUC ≥ 1,690 h*ng/mL for relapsed/refractory patients. Higher exposures were not associated with increases in severe adverse events (≥ grade 3).Conclusions: Pharmacokinetic modeling showed no difference in Flavopiridol plasma protein binding for bolus versus hybrid dosing. Further trials in newly diagnosed patients with acute leukemia should utilize the bolus FLAM regimen at the MTD of 50 mg/m2/day. Trials in relapsed/refractory patients should use the hybrid dosing schedule at the MTD (30/60 mg/m2/day) to achieve the higher exposures required for maximal efficacy in this population. Clin Cancer Res; 23(14); 3592-600. ©2017 AACR.

  • randomized phase ii study of two schedules of Flavopiridol given as timed sequential therapy with cytosine arabinoside and mitoxantrone for adults with newly diagnosed poor risk acute myelogenous leukemia
    Haematologica, 2012
    Co-Authors: Judith E. Karp, Jacqueline Greer, Michelle A Rudek, Douglas B Smith, Elizabeth Garrettmayer, Elihu H Estey, Michelle D Drye, Karen Mackey, Kathleen Shannon Dorcy, Steven D Gore
    Abstract:

    Background Flavopiridol is a protein-bound, cytotoxic, cyclin dependent kinase inhibitor. A phase II trial of Flavopiridol followed by ara-C and mitoxantrone with Flavopiridol given by 1-h bolus for adults with newly-diagnosed, poor-risk acute myelogenous leukemia yielded 67% complete remission with median disease-free survival of 13.6 months.Design and Methods We compared bolus Flavopiridol (50 mg/m2/day, Arm A) versus 'hybrid' Flavopiridol (30 mg/m2 over 30 min followed by 40 mg/m2 over 4 h, Arm B) followed by ara-C and mitoxantrone in 78 patients (39 per arm) with newly diagnosed, poor-risk acute myelogenous leukemia. To mitigate imbalance, patients were stratified by presence or absence of secondary leukemia and therapy for antecedent disorder.Results Death at or before Day 60 occurred in 8% of patients per arm. Complete remission plus complete remission with incomplete recovery was 68% (Arm A, 62%; Arm B, 74%) overall, and 65% or over in both arms for patients with secondary leukemia and leukemia with adverse genetics. In Arm A 91% and in Arm B 86% of patients received chemotherapy and/or allogeneic transplantation in complete remission. Median overall survival for all remission patients has not been reached for either arm, with median disease free survival of 13.6 months for Arm A and of 12.0 months for Arm B.Conclusions Both Flavopiridol schedules produce comparably encouraging results in adults with poor-risk acute myelogenous leukemia. Given the greater ease of bolus administration, we are conducting a randomized phase II study of bolus Flavopiridol followed by ara-c and mitoxantrone versus conventional induction therapy for patients aged 70 years and under with intermediate or poor-risk acute myelogenous leukemia. This study is registered at www.clinicaltrials.gov as #NCT 00407966.

  • Flavopiridol induces bcl 2 expression and represses oncogenic transcription factors in leukemic blasts from adults with refractory acute myeloid leukemia
    Leukemia & Lymphoma, 2011
    Co-Authors: Dwella M Nelson, Judith E. Karp, Biju Joseph, Joelle Hillion, Jodi B Segal, Linda M S Resar
    Abstract:

    Flavopiridol is a cyclin-dependent kinase inhibitor that induces cell cycle arrest, apoptosis, and clinical responses in selected patients with acute myeloid leukemia (AML). A better understanding of the molecular pathways targeted by Flavopiridol is needed to design optimal combinatorial therapy. Here, we report that in vivo administration of Flavopiridol induced expression of the BCL-2 anti-apoptotic gene in leukemic blasts from adult patients with refractory AML. Moreover, Flavopiridol repressed the expression of genes encoding oncogenic transcription factors (HMGA1, STAT3, E2F1) and the major subunit of RNA Polymerase II. Our results provide mechanistic insight into the cellular pathways targeted by Flavopiridol. Although further studies are needed, our findings also suggest that blocking anti-apoptotic pathways could enhance cytotoxicity with Flavopiridol.

  • phase 1 and pharmacokinetic study of bolus infusion Flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukemias
    Blood, 2011
    Co-Authors: Judith E. Karp, Jacqueline Greer, Douglas B Smith, Mark J Levis, Linda M S Resar, Amanda L Blackford, Ming Zhao, Dwella Motonnelson, Katrina Alino, Steven D Gore
    Abstract:

    Flavopiridol is a protein bound, cytotoxic, cyclin-dependent kinase inhibitor. Flavopiridol given by 1-hour bolus at 50 mg/m(2) daily 3 times followed by cytosine arabinoside and mitoxantrone (FLAM) is active in adults with poor-risk acute leukemias. A pharmacologically derived "hybrid" schedule (30-minute bolus followed by 4-hour infusion) of Flavopiridol was more effective than bolus administration in refractory chronic lymphocytic leukemia. Our phase 1 trial "hybrid FLAM" in 55 adults with relapsed/refractory acute leukemias began at a total Flavopiridol dose of 50 mg/m(2) per day 3 times (20-mg/m(2) bolus, 30-mg/m(2) infusion). Dose-limiting toxicity occurred at level 6 (30-mg/m(2) bolus, 70-mg/m(2) infusion) with tumor lysis, hyperbilirubinemia, and mucositis. Death occurred in 5 patients (9%). Complete remission occurred in 22 (40%) across all doses. Overall and disease-free survivals for complete remission patients are more than 60% at more than 2 years. Pharmacokinetics demonstrated a dose-response for total and unbound plasma Flavopiridol unrelated to total protein, albumin, peripheral blast count, or toxicity. Pharmacodynamically, Flavopiridol inhibited mRNAs of multiple cell cycle regulators, but with uniform increases in bcl-2. "Hybrid FLAM" is active in relapsed/refractory acute leukemias, with a recommended "hybrid" dose of bolus 30 mg/m(2) followed by infusion of 60 mg/m(2) daily for 3 days. This clinical trial is registered at www.clinicaltrials.gov as #NCT00470197.

  • sequential Flavopiridol cytosine arabinoside and mitoxantrone a phase ii trial in adults with poor risk acute myelogenous leukemia
    Clinical Cancer Research, 2007
    Co-Authors: Judith E. Karp, Jacqueline Greer, John J Wright, Douglas B Smith, Mark J Levis, Steven D Gore, Catherine Hattenburg, Janet Briel, Richard J Jones, Dimitri A Colevas
    Abstract:

    Purpose: Flavopiridol is a cyclin-dependent kinase inhibitor that is cytotoxic to leukemic blasts. In a phase I study of Flavopiridol followed by 1-β-d-arabinofuranosylcytosine (ara-C) and mitoxantrone, overall response rate for adults with relapsed and refractory acute myelogenous leukemias (AML) was 31%. We have now completed a phase II study of sequential Flavopiridol, ara-C, and mitoxantrone in 62 adults with poor-risk AML. Experimental Design: Flavopiridol (50 mg/m 2 ) was given by 1-h infusion daily × 3 beginning day 1 followed by 2 gm/m 2 /72 h ara-C beginning day 6 and 40 mg/m 2 mitoxantrone on day 9. Results: Flavopiridol caused a ≥50% decrease in peripheral blood blasts in 44% by median day 2 and ≥80% decrease in 26% by day 3. Self-limited tumor lysis occurred in 53%. Three (5%) died during therapy (2 multiorgan failure and 1 fungal pneumonia). Complete remissions (CR) were achieved in 12 of 15 (75%) newly diagnosed secondary AML, 18 of 24 (75%) first relapse after short CR (median CR, 9 months, including prior allotransplant), and 2 of 13 (15%) primary refractory but 0 of 10 multiply refractory AML. Disease-free survival for all CR patients is 40% at 2 years, with newly diagnosed patients having a 2-year disease-free survival of 50%. Conclusions: Flavopiridol has anti-AML activity directly and in combination with ara-C and mitoxantrone. This timed sequential regimen induces durable CRs in a significant proportion of adults with newly diagnosed secondary AML (including complex cytogenetics) and adults with AML in first relapse after short first CR.

Edward A. Sausville - One of the best experts on this subject based on the ideXlab platform.

  • Clinical Pharmacology of Flavopiridol Following a 72-Hour Continuous Infusion
    2016
    Co-Authors: Michelle A Rudek, Adrian M. Senderowicz, Kenneth S Bauer, Richard M Lush, Sherman F Stinson, Donna J Headlee, Susan G Arbuck, Michael C Cox, Anthony J Murgo, Edward A. Sausville
    Abstract:

    Flavopiridol is a novel flavone compound syntheticallyderived from a parent compound isolated from Dysoxy-lum binectariferum. In vitro studies have demonstrated that Flavopiridol inhibits cyclin-dependent kinase-1 (CDK1), the mediator of cell-cycle progression from G2 to M phase.1 Additional studies have also found that Flavopiridol is an inhibitor of CDK2, whose activity appears at the G1-S boundary.2 In addition, Flavopiridol has antiangiogenic activity and does not exhibit multidrug resistance in vitro.3 Based on this unique spectrum of in vitro activity, 4 Phase I studies and several Phase II clinical trials were initiated. We initiated a Phase I trial of Flavopiridol in patients with refractory solid tumors to determine the maximum tolerated dose and characterize the adverse effect profile.4 Secretory diarrhea was the dose-limiting toxicity when Flavopiridol was administered as a 72-hour continuous in-fusion every 2 weeks. Several different treatment and pro-phylactic regimens were tested to ameliorate the diarrhea. The best of these consisted of cholestyramine and lo-peramide. Nonetheless, Flavopiridol was well tolerated at doses of 50 mg/m2/d for 3 days without antidiarrheal pro-phylaxis and 78 mg/m2/d for 3 days with prophylaxis. Flavopiridol has entered widespread Phase II testing, with Phase III trials being planned. This article describes the clinical and laboratory studies conducted to characterize the clinical pharmacology of Flavopiridol from this trial. In addition, we explored the importance of enterohepatic re

  • phase i clinical and pharmacokinetic study of Flavopiridol administered as a daily 1 hour infusion in patients with advanced neoplasms
    Journal of Clinical Oncology, 2002
    Co-Authors: Antoinette R Tan, Edward A. Sausville, Giovanni Melillo, Susan G Arbuck, Anthony J Murgo, Donna Headlee, Richard A Messmann, Suoping Zhai, William D Figg, Sandra M Swain
    Abstract:

    PURPOSE: To define the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of the cyclin-dependent kinase inhibitor Flavopiridol administered as a daily 1-hour infusion every 3 weeks. PATIENTS AND METHODS: Fifty-five patients with advanced neoplasms were treated with Flavopiridol at doses of 12, 17, 24, 30, 37.5, and 52.5 mg/m2/d for 5 days; doses of 50 and 62.5 mg/m2/d for 3 days; and doses of 62.5 and 78 mg/m2/d for 1 day. Plasma sampling was performed to characterize the pharmacokinetics of Flavopiridol with these schedules. RESULTS: Dose-limiting neutropenia developed at doses ≥ 52.5 mg/m2/d. Nonhematologic toxicities included nausea, vomiting, diarrhea, hypotension, and a proinflammatory syndrome characterized by anorexia, fatigue, fever, and tumor pain. The median peak concentrations of Flavopiridol achieved at the MTDs on the 5-day, 3-day, and 1-day schedule were 1.7 μmol/L (range, 1.3 to 4.2 μmol/L), 3.2 μmol/L (range, 1.7 to 4.8 μmol/L), and 3.9 μmol/L (1.8 to 5.1 μmol/L), ...

  • Flavopiridol a novel cyclin dependent kinase inhibitor in clinical development
    Annals of Pharmacotherapy, 2002
    Co-Authors: Suoping Zhai, Edward A. Sausville, Adrian M. Senderowicz, William D Figg
    Abstract:

    OBJECTIVE:To review preclinical and clinical information on Flavopiridol, an inhibitor of cyclin-dependent kinases (CDKs), tested as an antitumor agent.DATA SOURCES:Primary and review articles were identified by MEDLINE search (1990–June 2001). Abstracts from recent meetings were also used as source materials.DATA EXTRACTION:Flavopiridol was reviewed with regard to its mechanisms, preclinical and clinical results, pharmacokinetics, and metabolism.DATA SYNTHESIS:Flavopiridol is an inhibitor of several CDKs and displays unique anticancer properties. In addition to direct CDK inhibition, Flavopiridol also exhibited other features such as inducing apoptosis in many cancer cell lines, decreasing cyclin D1 concentration, and inhibiting angiogenesis. Preclinical xenograft models showed significant antitumor activity for Flavopiridol. The regimen using 72-hour continuous infusion every 2 weeks has been most extensively applied in clinical trials, with a 1-hour infusion currently being explored to achieve higher p...

  • Flavopiridol inhibits P-TEFb and blocks HIV-1 replication.
    Journal of Biological Chemistry, 2000
    Co-Authors: Shenghao Chao, David H Price, Koh Fujinaga, B. Matija Peterlin, Jon E. Marion, Edward A. Sausville, Adrian M. Senderowicz
    Abstract:

    Flavopiridol (L86-8275, HMR1275) is a cyclin-dependent kinase (Cdk) inhibitor that is in clinical trials as a cancer treatment because of its antiproliferative properties. We found that the flavonoid potently inhibited transcription by RNA polymerase II in vitro by blocking the transition into productive elongation, a step controlled by P-TEFb. The ability of P-TEFb to phosphorylate the carboxyl-terminal domain of the large subunit of RNA polymerase II was inhibited by Flavopiridol with a K(i) of 3 nm. Interestingly, the drug was not competitive with ATP. P-TEFb composed of Cdk9 and cyclin T1 is a required cellular cofactor for the human immunodeficiency virus (HIV-1) transactivator, Tat. Consistent with its ability to inhibit P-TEFb, Flavopiridol blocked Tat transactivation of the viral promoter in vitro. Furthermore, Flavopiridol blocked HIV-1 replication in both single-round and viral spread assays with an IC(50) of less than 10 nm.

  • Flavopiridol a protein kinase inhibitor down regulates hypoxic induction of vascular endothelial growth factor expression in human monocytes
    Cancer Research, 1999
    Co-Authors: Giovanni Melillo, Edward A. Sausville, Tyler Lahusen, Kiona Cloud, Luigi Varesio, Adrian M. Senderowicz
    Abstract:

    We have investigated the effects of Flavopiridol, a novel protein kinase inhibitor that is selective for cyclin-dependent kinases, on hypoxia-induced vascular endothelial growth factor (VEGF) expression in human monocytes. We found that hypoxia induces a time-dependent increase of VEGF mRNA expression and protein levels in human monocytes. Flavopiridol showed a minimal effect on the constitutive levels of VEGF mRNA but completely blocked hypoxia-induced VEGF mRNA and protein expression. The inhibitory effects of Flavopiridol on VEGF mRNA induction also occurred in the presence of cycloheximide. The transcriptional activation of either a VEGF promoter-luciferase construct or a hypoxia-inducible factor 1 reporter plasmid was not affected by addition of Flavopiridol in transient transfection experiments. In contrast, actinomycin D experiments demonstrated that Flavopiridol dramatically decreased VEGF mRNA stability. These data provide the first evidence that Flavopiridol can affect gene expression by altering mRNA stability. We propose that Flavopiridol may interfere with one or more signaling events, leading to hypoxia-induced, protein kinase-modulated, RNA protein binding activity. An important clinical implication of our results is that Flavopiridol, presently under investigation in clinical trials, might have antiangiogenic as well as direct antiproliferative effects.

Jacqueline Greer - One of the best experts on this subject based on the ideXlab platform.

  • exposure response analysis of alvocidib Flavopiridol treatment by bolus or hybrid administration in newly diagnosed or relapsed refractory acute leukemia patients
    Clinical Cancer Research, 2017
    Co-Authors: Carl Lacerte, Judith E. Karp, Vijay Ivaturi, Jogarao V S Gobburu, Jacqueline Greer, Austin Doyle, John J Wright, Michelle A Rudek
    Abstract:

    Purpose: To elucidate any differences in the exposure-response of alvocidib (Flavopiridol) given by 1-hour bolus or a hybrid schedule (30-minute bolus followed by a 4-hour infusion) using a Flavopiridol/cytosine arabinoside/mitoxantrone sequential protocol (FLAM) in patients with acute leukemia. The hybrid schedule was devised to be pharmacologically superior in chronic leukemia based on unbound exposure.Experimental Design: Data from 129 patients in three FLAM studies were used for pharmacokinetic/pharmacodynamic modeling. Newly diagnosed (62%) or relapsed/refractory (38%) patients were treated by bolus (43%) or hybrid schedule (57%). Total and unbound Flavopiridol concentrations were fit using nonlinear mixed-effect population pharmacokinetic methodologies. Exposure-response relationships using unbound Flavopiridol AUC were explored using recursive partitioning.Results: Flavopiridol pharmacokinetic parameters were estimated using a two-compartment model. No pharmacokinetic covariates were identified. Flavopiridol fraction unbound was 10.9% and not different between schedules. Partitioning found no association between dosing schedule and clinical response. Clinical response was associated with AUC ≥ 780 h*ng/mL for newly diagnosed patients and AUC ≥ 1,690 h*ng/mL for relapsed/refractory patients. Higher exposures were not associated with increases in severe adverse events (≥ grade 3).Conclusions: Pharmacokinetic modeling showed no difference in Flavopiridol plasma protein binding for bolus versus hybrid dosing. Further trials in newly diagnosed patients with acute leukemia should utilize the bolus FLAM regimen at the MTD of 50 mg/m2/day. Trials in relapsed/refractory patients should use the hybrid dosing schedule at the MTD (30/60 mg/m2/day) to achieve the higher exposures required for maximal efficacy in this population. Clin Cancer Res; 23(14); 3592-600. ©2017 AACR.

  • randomized phase ii study of two schedules of Flavopiridol given as timed sequential therapy with cytosine arabinoside and mitoxantrone for adults with newly diagnosed poor risk acute myelogenous leukemia
    Haematologica, 2012
    Co-Authors: Judith E. Karp, Jacqueline Greer, Michelle A Rudek, Douglas B Smith, Elizabeth Garrettmayer, Elihu H Estey, Michelle D Drye, Karen Mackey, Kathleen Shannon Dorcy, Steven D Gore
    Abstract:

    Background Flavopiridol is a protein-bound, cytotoxic, cyclin dependent kinase inhibitor. A phase II trial of Flavopiridol followed by ara-C and mitoxantrone with Flavopiridol given by 1-h bolus for adults with newly-diagnosed, poor-risk acute myelogenous leukemia yielded 67% complete remission with median disease-free survival of 13.6 months.Design and Methods We compared bolus Flavopiridol (50 mg/m2/day, Arm A) versus 'hybrid' Flavopiridol (30 mg/m2 over 30 min followed by 40 mg/m2 over 4 h, Arm B) followed by ara-C and mitoxantrone in 78 patients (39 per arm) with newly diagnosed, poor-risk acute myelogenous leukemia. To mitigate imbalance, patients were stratified by presence or absence of secondary leukemia and therapy for antecedent disorder.Results Death at or before Day 60 occurred in 8% of patients per arm. Complete remission plus complete remission with incomplete recovery was 68% (Arm A, 62%; Arm B, 74%) overall, and 65% or over in both arms for patients with secondary leukemia and leukemia with adverse genetics. In Arm A 91% and in Arm B 86% of patients received chemotherapy and/or allogeneic transplantation in complete remission. Median overall survival for all remission patients has not been reached for either arm, with median disease free survival of 13.6 months for Arm A and of 12.0 months for Arm B.Conclusions Both Flavopiridol schedules produce comparably encouraging results in adults with poor-risk acute myelogenous leukemia. Given the greater ease of bolus administration, we are conducting a randomized phase II study of bolus Flavopiridol followed by ara-c and mitoxantrone versus conventional induction therapy for patients aged 70 years and under with intermediate or poor-risk acute myelogenous leukemia. This study is registered at www.clinicaltrials.gov as #NCT 00407966.

  • phase 1 and pharmacokinetic study of bolus infusion Flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukemias
    Blood, 2011
    Co-Authors: Judith E. Karp, Jacqueline Greer, Douglas B Smith, Mark J Levis, Linda M S Resar, Amanda L Blackford, Ming Zhao, Dwella Motonnelson, Katrina Alino, Steven D Gore
    Abstract:

    Flavopiridol is a protein bound, cytotoxic, cyclin-dependent kinase inhibitor. Flavopiridol given by 1-hour bolus at 50 mg/m(2) daily 3 times followed by cytosine arabinoside and mitoxantrone (FLAM) is active in adults with poor-risk acute leukemias. A pharmacologically derived "hybrid" schedule (30-minute bolus followed by 4-hour infusion) of Flavopiridol was more effective than bolus administration in refractory chronic lymphocytic leukemia. Our phase 1 trial "hybrid FLAM" in 55 adults with relapsed/refractory acute leukemias began at a total Flavopiridol dose of 50 mg/m(2) per day 3 times (20-mg/m(2) bolus, 30-mg/m(2) infusion). Dose-limiting toxicity occurred at level 6 (30-mg/m(2) bolus, 70-mg/m(2) infusion) with tumor lysis, hyperbilirubinemia, and mucositis. Death occurred in 5 patients (9%). Complete remission occurred in 22 (40%) across all doses. Overall and disease-free survivals for complete remission patients are more than 60% at more than 2 years. Pharmacokinetics demonstrated a dose-response for total and unbound plasma Flavopiridol unrelated to total protein, albumin, peripheral blast count, or toxicity. Pharmacodynamically, Flavopiridol inhibited mRNAs of multiple cell cycle regulators, but with uniform increases in bcl-2. "Hybrid FLAM" is active in relapsed/refractory acute leukemias, with a recommended "hybrid" dose of bolus 30 mg/m(2) followed by infusion of 60 mg/m(2) daily for 3 days. This clinical trial is registered at www.clinicaltrials.gov as #NCT00470197.

  • sequential Flavopiridol cytosine arabinoside and mitoxantrone a phase ii trial in adults with poor risk acute myelogenous leukemia
    Clinical Cancer Research, 2007
    Co-Authors: Judith E. Karp, Jacqueline Greer, John J Wright, Douglas B Smith, Mark J Levis, Steven D Gore, Catherine Hattenburg, Janet Briel, Richard J Jones, Dimitri A Colevas
    Abstract:

    Purpose: Flavopiridol is a cyclin-dependent kinase inhibitor that is cytotoxic to leukemic blasts. In a phase I study of Flavopiridol followed by 1-β-d-arabinofuranosylcytosine (ara-C) and mitoxantrone, overall response rate for adults with relapsed and refractory acute myelogenous leukemias (AML) was 31%. We have now completed a phase II study of sequential Flavopiridol, ara-C, and mitoxantrone in 62 adults with poor-risk AML. Experimental Design: Flavopiridol (50 mg/m 2 ) was given by 1-h infusion daily × 3 beginning day 1 followed by 2 gm/m 2 /72 h ara-C beginning day 6 and 40 mg/m 2 mitoxantrone on day 9. Results: Flavopiridol caused a ≥50% decrease in peripheral blood blasts in 44% by median day 2 and ≥80% decrease in 26% by day 3. Self-limited tumor lysis occurred in 53%. Three (5%) died during therapy (2 multiorgan failure and 1 fungal pneumonia). Complete remissions (CR) were achieved in 12 of 15 (75%) newly diagnosed secondary AML, 18 of 24 (75%) first relapse after short CR (median CR, 9 months, including prior allotransplant), and 2 of 13 (15%) primary refractory but 0 of 10 multiply refractory AML. Disease-free survival for all CR patients is 40% at 2 years, with newly diagnosed patients having a 2-year disease-free survival of 50%. Conclusions: Flavopiridol has anti-AML activity directly and in combination with ara-C and mitoxantrone. This timed sequential regimen induces durable CRs in a significant proportion of adults with newly diagnosed secondary AML (including complex cytogenetics) and adults with AML in first relapse after short first CR.

  • phase i and pharmacokinetic study of Flavopiridol followed by 1 β d arabinofuranosylcytosine and mitoxantrone in relapsed and refractory adult acute leukemias
    Clinical Cancer Research, 2005
    Co-Authors: Judith E. Karp, Jacqueline Greer, Janet Briel, Keith C Bible, Scott H Kaufmann, Ivana Gojo, Antonino Passaniti, Tushar S Garimella, Douglas B Smith
    Abstract:

    Purpose: The serine/threonine kinase inhibitor Flavopiridol targets multiple cyclin-dependent kinases, induces checkpoint arrest, and interrupts transcriptional elongation. We designed a phase I clinical trial using a timed sequential therapy approach where Flavopiridol was given for the dual purpose of initial cytoreduction and enhancing cell cycle progression of the remaining leukemia cell cohort followed by cycle-dependent drugs 1-β-d-arabinofuranosylcytosine (ara-C) and mitoxantrone. Experimental Design: Flavopiridol was given by 1-hour infusion daily for 3 days beginning day 1 followed by 2 g/m 2 /72 h ara-C beginning day 6 and 40 mg/m 2 mitoxantrone beginning day 9. In vivo correlates included pharmacokinetics, modulation of blast cycle regulators, and serum and marrow supernatant vascular endothelial growth factor levels. Results: Of 34 adults receiving induction therapy, 16 (47%) evinced direct leukemia cytotoxicity with ≥50% drop in peripheral blast counts and tumor lysis in 9 (26%). Four (12%) died during therapy (two fungal infections and two sudden death). Dose-limiting toxicity occurred at 60 mg/m 2 /d with profound neutropenia >40 days duration, and maximal tolerated dose was 50 mg/m 2 /d. Overall response rate was 31% in 26 acute myelogenous leukemia and 12.5% in acute lymphoblastic leukemia. Pharmacokinetics showed that a linear two-compartment model with first-order elimination provided the best fit of the observed concentration versus time data. Flavopiridol down-regulated one or more target proteins in marrow blasts in vivo . Vascular endothelial growth factor was detected in sera and marrow supernatant pretreatment, and sera obtained on day 3 inhibited bovine aortic endothelial cell proliferation by a mean of 32% (range, 10-80%). Conclusions: Our data suggest that Flavopiridol is cytotoxic to leukemic cells and, when followed by ara-C and mitoxantrone, exerts biological and clinical effects in patients with relapsed and refractory acute leukemias. These findings warrant continuing development of Flavopiridol at 50 mg/m 2 /d × 3 days in combination with cytotoxic and biological agents for acute leukemias.

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  • mechanism and functional role of xiap and mcl 1 down regulation in Flavopiridol vorinostat antileukemic interactions
    Cancer Research, 2007
    Co-Authors: Roberto R Rosato, Jorge A Almenara, Sarah S Kolla, Sonia C Maggio, Stefanie Coe, Maria S Gimenez, Paul Dent, Steven Grant
    Abstract:

    AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 3213 The mechanism and functional significance of XIAP and Mcl-1 down-regulation in human leukemia cells exposed to the HDAC inhibitor vorinostat and the CDK inhibitor Flavopiridol was investigated. Combined exposure of U937 leukemia cells to marginally toxic concentrations of vorinostat and Flavopiridol resulted in a marked increase in mitochondrial damage and apoptosis accompanied by pronounced reductions in XIAP and Mcl-1 mRNA and protein. Down-regulation of Mcl-1 and XIAP expression by vorinostat/Flavopiridol was associated with enhanced inhibition of phosphorylation of RNA PolII and was amplified by caspase-mediated protein degradation. Chromatin immunoprecipitation (ChIP) analysis revealed that XIAP and Mcl-1 down-regulation were also accompanied by both decreased association of NF-κB (XIAP) and increased E2F1 association (Mcl-1) with their promoter regions, respectively. Ectopic expression of Mcl-1 but not XIAP partially protected cells from Flavopiridol/vorinostat-mediated mitochondrial injury at 48 hr, but neither significantly restored clonogenic potential. Flavopiridol/vorinostat-mediated transcriptional repression of XIAP and Mcl-1, enhanced apoptosis, and loss of clonogenic potential also occurred in primary AML blasts. Together, these findings indicate that transcriptional repression of XIAP and Mcl-1 by Flavopiridol/vorinostat contributes functionally to apoptosis induction at early exposure intervals, and raise the possibility that expression levels may be a useful surrogate marker for activity in current trials.

  • mechanism and functional role of xiap and mcl 1 down regulation in Flavopiridol vorinostat antileukemic interactions
    Molecular Cancer Therapeutics, 2007
    Co-Authors: Roberto R Rosato, Jorge A Almenara, Sarah S Kolla, Sonia C Maggio, Stefanie Coe, Maria S Gimenez, Paul Dent, Steven Grant
    Abstract:

    The mechanism and functional significance of XIAP and Mcl-1 down-regulation in human leukemia cells exposed to the histone deacetylase inhibitor vorinostat and the cyclin-dependent kinase inhibitor Flavopiridol was investigated. Combined exposure of U937 leukemia cells to marginally toxic concentrations of vorinostat and Flavopiridol resulted in a marked increase in mitochondrial damage and apoptosis accompanied by pronounced reductions in XIAP and Mcl-1 mRNA and protein. Down-regulation of Mcl-1 and XIAP expression by vorinostat/Flavopiridol was associated with enhanced inhibition of phosphorylation of RNA polymerase II and was amplified by caspase-mediated protein degradation. Chromatin immunoprecipitation analysis revealed that XIAP and Mcl-1 down-regulation were also accompanied by both decreased association of nuclear factor-κB (XIAP) and increased E2F1 association (Mcl-1) with their promoter regions, respectively. Ectopic expression of Mcl-1 but not XIAP partially protected cells from Flavopiridol/vorinostat–mediated mitochondrial injury at 48 h, but both did not significantly restored clonogenic potential. Flavopiridol/vorinostat–mediated transcriptional repression of XIAP, Mcl-1–enhanced apoptosis, and loss of clonogenic potential also occurred in primary acute myelogenous leukemia (AML) blasts. Together, these findings indicate that transcriptional repression of XIAP and Mcl-1 by Flavopiridol/vorinostat contributes functionally to apoptosis induction at early exposure intervals and raise the possibility that expression levels may be a useful surrogate marker for activity in current trials. [Mol Cancer Ther 2007;6(2):692–702]

  • bortezomib and Flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both bcr abl dependent and independent mechanisms
    Blood, 2004
    Co-Authors: Yun Dai, Paul Dent, Mohamed Rahmani, Xinyan Pei, Steven Grant
    Abstract:

    Interactions between the cyclin-dependent kinase (CDK) inhibitor Flavopiridol and the proteasome inhibitor bortezomib were examined in Bcr/Abl(+) human leukemia cells. Coexposure of K562 or LAMA84 cells to subtoxic concentration of Flavopiridol (150-200 nM) and bortezomib (5-8 nM) resulted in a synergistic increase in mitochondrial dysfunction and apoptosis. These events were associated with a marked diminution in nuclear factor kappaB (NF-kappaB)/DNA binding activity; enhanced phosphorylation of SEK1/MKK4 (stress-activated protein kinase/extracellular signal-related kinase 1/mitogen-activated protein kinase kinase 4), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK); down-regulation of Bcr/Abl; and a marked reduction in signal transducer and activator of transcription 3 (STAT3) and STAT5 activity. In imatinib mesylate-resistant K562 cells displaying increased Bcr/Abl expression, bortezomib/Flavopiridol treatment markedly increased apoptosis in association with down-regulation of Bcr/Abl and BclxL, and diminished phosphorylation of Lyn, Hck, CrkL, and Akt. Parallel studies were performed in imatinib mesylate-resistant LAMA84 cells exhibiting reduced expression of Bcr/Abl but a marked increase in expression/activation of Lyn and Hck. Flavopiridol/bortezomib effectively induced apoptosis in these cells in association with Lyn and Hck inactivation. The capacity of Flavopiridol to promote bortezomib-mediated Bcr/Abl down-regulation and apoptosis was mimicked by the positive transcription elongation factor-b (P-TEFb) inhibitor DRB (5,6-dichloro 1-beta-d-ribofuranosylbenzinida-sole). Finally, the bortezomib/Flavopiridol regimen also potently induced apoptosis in Bcr/Abl(-) human leukemia cells. Collectively, these findings suggest that a strategy combining Flavopiridol and bortezomib warrants further examination in chronic myelogenous leukemia and related hematologic malignancies.

  • proteasome inhibitors potentiate leukemic cell apoptosis induced by the cyclin dependent kinase inhibitor Flavopiridol through a sapk jnk and nf κb dependent process
    Oncogene, 2003
    Co-Authors: Yun Dai, Mohamed Rahmani, Steven Grant
    Abstract:

    Interactions between proteasome and cyclin-dependent kinase inhibitors have been examined in human leukemia cells in relation to induction of apoptosis. Simultaneous exposure (24 h) of U937 myelomonocytic leukemia cells to 100 nM Flavopiridol and 300 nM MG-132 resulted in a marked increase in mitochondrial injury (cytochrome c, Smac/DIABLO release, loss of deltaPsi(m)), caspase activation, and synergistic induction of cell death, accompanied by a marked decrease in clonogenic potential. Similar effects were observed with other proteasome inhibitors (e.g., Bortezomib (VELCADE trade mark bortezomib or injection), lactacystin, LLnL) and cyclin-dependent kinase inhibitors (e.g., roscovitine), as well as other leukemia cell types (e.g., HL-60, Jurkat, Raji). In U937 cells, synergistic interactions between MG-132 and Flavopiridol were associated with multiple perturbations in expression/activation of signaling- and survival-related proteins, including downregulation of XIAP and Mcl-1, activation of JNK and p34(cdc2), and diminished expression of p21(CIP1). The lethal effects of MG-132/Flavopiridol were not reduced in leukemic cells ectopically expressing Bcl-2, but were partially attenuated in cells ectopically expressing dominant-negative caspase-8 or CrmA. Flavopiridol/proteasome inhibitor-mediated lethality was also significantly diminished by agents and siRNA blocking JNK activation. Lastly, coadministration of MG-132 with Flavopiridol resulted in diminished DNA binding of NF-kappaB. Notably, pharmacologic interruption of the NF-kappaB pathway (e.g., by BAY 11-7082, PDTC, or SN-50) or molecular dysregulation of NF-kappaB (i.e., in cells ectopically expressing an IkappaBalpha super-repressor) mimicked the actions of proteasome inhibitors in promoting Flavopiridol-induced mitochondrial injury, JNK activation, and apoptosis. Together, these findings indicate that proteasome inhibitors strikingly lower the apoptotic threshold of leukemic cells exposed to pharmacologic CDK inhibitors, and suggest that interruption of the NF-kappaB cytoprotective pathway and JNK activation both play key roles in this phenomenon. They also raise the possibility that combining proteasome and CDK inhibitors could represent a novel antileukemic strategy.

  • Flavopiridol potentiates sti571 induced mitochondrial damage and apoptosis in bcr abl positive human leukemia cells
    Clinical Cancer Research, 2002
    Co-Authors: Geoffrey W Krystal, Paul Dent, Steven Grant
    Abstract:

    Purpose: The goal of this study was to characterize interactions between the Bcr/Abl kinase inhibitor STI571 and the cyclin-dependent kinase inhibitor Flavopiridol in Bcr/Abl + human leukemia cells. Experimental Design: K562 leukemia cells were exposed to STI571 ± Flavopiridol for 24 or 48 h, after which mitochondrial damage, caspase activation, expression/activation of signaling and cell cycle regulatory proteins, and apoptosis were assessed. Results: In K562 cells, coadministration of marginally toxic concentrations of STI571 (200 nm) and Flavopiridol (150 nm) for 48 h resulted in a marked increase in mitochondrial damage ( e.g. , cytochrome c release), activation of caspase-3, caspase-8, and Bid, and apoptosis. Similar interactions were observed in Bcr/Abl + LAMA-84 cells but not in leukemic cells that fail to express Bcr/Abl ( e.g. , HL-60, U937, Jurkat). STI571/Flavopiridol-mediated apoptosis was associated with the caspase-independent down-regulation of Bcl-x L and Mcl-1, activation of extracellular signal-regulated kinase and c-Jun NH 2 -terminal kinase, and the caspase-dependent release of Smac/DIABLO and loss of Δψ m . Coadministration of Flavopiridol and STI571 did not result in changes in levels of expression of Bcl-2, phopho-Stat5, phospho-p34 cdc2 , or Bcr/Abl. Finally, STI571/Flavopiridol effectively induced apoptosis in STI571-resistant K562 cells displaying amplification of the Bcr/Abl protein. Conclusions: Together, these findings indicate that the cyclin-dependent kinase inhibitor Flavopiridol induces multiple perturbations in signaling pathways in STI571-treated Bcr/Abl + human leukemia cells that culminate in mitochondrial injury, caspase activation, and apoptosis. They also suggest that simultaneous disruption of survival signaling and cell cycle regulatory pathways may represent an effective strategy in Bcr/Abl + malignancies.