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Richard L. Momparler - One of the best experts on this subject based on the ideXlab platform.

  • www.mdpi.com/journal/pharmaceuticals Review A Perspective on the Comparative Antileukemic Activity of
    2012
    Co-Authors: Richard L. Momparler
    Abstract:

    (5-AC, Vidaza®) are epigenetic Agents that have been approved for the clinical treatment of the hematological malignancy myelodysplastic syndrome (MDS) and are currently under clinical evaluation for the treatment of acute myeloid leukemia (AML). Most investigators currently classify 5-AZA-CdR and 5-AC as inhibitors of DNA methylation, which can reactivate tumor suppressor genes silenced by this epigenetic event. Examination of the pharmacology of these analogues reveals important differences with respect to their molecular mechanism of action. The action of 5-AZA-CdR is due to its incorporation into DNA. 5-AC is a riboside analogue that is incorporated primarily into RNA. A small fraction of 5-AC is converted to its deoxyribose form by ribonucleotide reductase and subsequently incorporated into DNA. The incorporation of 5-AC into RNA can interfere with the biological function of RNA and result in an inhibition protein synthesis. Microarray analysis revealed that both these analogues target the expression of different cohorts of genes. Preclinical studies show that 5-AZA-CdR is a more effective Antileukemic Agent than 5-AC. One explanation for this observation is that 5-AC blocks the progression of some leukemic cells from G1 into S phase, and this protects these cells fro

  • A Perspective on the Comparative Antileukemic Activity of 5-Aza-2′-deoxycytidine (Decitabine) and 5-Azacytidine (Vidaza)
    MDPI AG, 2012
    Co-Authors: Richard L. Momparler
    Abstract:

    5-Aza-2′-deoxycytidine (5-AZA-CdR, decitabine, Dacogen®) and 5-azacytidine (5-AC, Vidaza®) are epigenetic Agents that have been approved for the clinical treatment of the hematological malignancy myelodysplastic syndrome (MDS) and are currently under clinical evaluation for the treatment of acute myeloid leukemia (AML). Most investigators currently classify 5-AZA-CdR and 5-AC as inhibitors of DNA methylation, which can reactivate tumor suppressor genes silenced by this epigenetic event. Examination of the pharmacology of these analogues reveals important differences with respect to their molecular mechanism of action. The action of 5-AZA-CdR is due to its incorporation into DNA. 5-AC is a riboside analogue that is incorporated primarily into RNA. A small fraction of 5-AC is converted to its deoxyribose form by ribonucleotide reductase and subsequently incorporated into DNA. The incorporation of 5-AC into RNA can interfere with the biological function of RNA and result in an inhibition protein synthesis. Microarray analysis revealed that both these analogues target the expression of different cohorts of genes. Preclinical studies show that 5-AZA-CdR is a more effective Antileukemic Agent than 5-AC. One explanation for this observation is that 5-AC blocks the progression of some leukemic cells from G<sub>1</sub> into S phase, and this protects these cells from the chemotherapeutic action of this riboside analogue related to its incorporation<strong> </strong>into DNA. However, differences in chemotherapeutic efficacy of these related analogues have not been clearly demonstrated in clinical trials in patients with hematological malignancies. These observations should be taken into consideration in the design of new clinical trials using 5-AZA-CdR or 5-AC in patients with MDS and AML

  • pharmacology of 5 aza 2 deoxycytidine decitabine
    Seminars in Hematology, 2005
    Co-Authors: Richard L. Momparler
    Abstract:

    The preclinical pharmacology of 5-aza-2′-deoxycytidine (decitabine, 5AZA-CdR) is reviewed. 5AZA-CdR, an analogue of deoxycytidine, is a prodrug that requires metabolic activation by deoxycytidine kinase. The active inhibitor in the cell is its triphosphate form (5AZA-dCTP), which incorporates very readily into DNA to produce an inhibition of DNA methyltransferase. The mechanism responsible for the Antileukemic action of 5AZA-CdR is related to its reversal of epigenetic silencing by aberrant DNA methylation of genes that suppress leukemiogenesis. 5AZA-CdR is an S-phase-specific Agent. At concentrations in the range of micromolars this analogue can induce terminal differentiation and loss of clonogenicity of human leukemic cells. Drug resistance to 5AZA-CdR occurs primarily by reduction in deoxycytidine kinase activity or increase in the activity of cytidine deaminase, the enzyme that inactivates this analogue. 5AZA-CdR is a very potent Antileukemic Agent in animal models, more effective than the related Antileukemic drug, cytosine arabinoside. In humans, 5AZA-CdR has a short half-life of 15 to 25 minutes due to rapid inactivation by liver cytidine deaminase. The major toxicity produced by 5AZA-CdR is myelosuppression. Preliminary clinical studies in patients with hematologic malignancies indicate that 5AZA-CdR is an active chemotherapeutic Agent. The optimal dose-schedule for this interesting epigenetic Agent with a novel mechanism of action remains to be determined. Translation of the pharmacology of 5AZA-CdR into therapeutic regimens based on scientific rationale can be used to obtain this objective.

  • preclinical evaluation of antineoplastic activity of inhibitors of dna methylation 5 aza 2 deoxycytidine and histone deacetylation trichostatin a depsipeptide in combination against myeloid leukemic cells
    Leukemia Research, 2003
    Co-Authors: Sepideh Shaker, Mark L Bernstein, Louise F Momparler, Richard L. Momparler
    Abstract:

    Abstract During the development of leukemia, genes that suppress growth and induce differentiation can be silenced by aberrant DNA methylation and by changes in chromatin structure that involve histone deacetylation. It has been reported that a positive interaction between DNA methylation and histone deacetylation takes place to inhibit transcription. Based on this observation, our working hypothesis was that a combination of inhibitors of these processes should produce an enhancement of their antineoplastic activity on leukemic cells. The cytosine nucleoside analog, 5-aza-2′-deoxycytidine (5AZA), is a potent inhibitor of DNA methylation, which can activate tumor suppressor genes in leukemic cells that have been silenced by aberrant methylation. In clinical trials, 5AZA was demonstrated to be an active Antileukemic Agent. Histone deacetylase inhibitors (HDI) can also activate gene expression in leukemic cell lines by producing changes in chromatin configuration, and show antineoplastic activity in preclinical studies. In this report, we investigated the in vitro antineoplastic activity of 5AZA, alone and in combination with the HDI, trichostatin A (TSA) and depsipeptide (FR901228, depsi), on the human myeloid leukemic cell lines, HL-60 and KG1a. The results showed that the combination of 5AZA with TSA or depsi produced a greater inhibition of growth and DNA synthesis and a greater loss of clonogenicity than either Agent alone. These results suggest that 5AZA used in combination with HDI may be an interesting chemotherapeutic regimen to investigate in patients with acute myeloid leukemia that is resistant to conventional chemotherapy.

Fatih M Uckun - One of the best experts on this subject based on the ideXlab platform.

  • in vivo toxicity and antithrombotic profile of the oral formulation of the Antileukemic Agent lfm a13 f
    Drug Research, 2011
    Co-Authors: Heather E Tibbles, P Samuel, Doug Erbeck, Sandeep Mahajan, Fatih M Uckun
    Abstract:

    The specific inhibitor of the protein tyrosine kinase, Bruton's tyrosine kinase (BTK), alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)-propenamide (LFM-A13, CAS 244240-24-2), is a chemosensitizing Antileukemic Agent with antithrombotic properties. Oral formulation of LFM-A13 (LFM-A13-F) did not cause acute, subacute or chronic toxicity in mice at dose levels up to 200 mg/kg. The in vivo antithrombotic activity of LFM-A13 was studied in a mouse model of collagen-induced fatal thromboembolism. Oral doses of LFM-A13-F dose dependently prevented collagen-induced thromboembolism in mice without causing bleeding. LFM-A13 could be combined with dipyridamole (CAS 58-32-2) without side effects. These results indicate that LFM-A13 may be particularly useful in the treatment of leukemia patients who are at risk for thromboembolic complications.

  • in vivo pharmacokinetic features toxicity profile and chemosensitizing activity of alpha cyano beta hydroxy beta methyl n 2 5 dibromophenyl propenamide lfm a13 a novel Antileukemic Agent targeting bruton s tyrosine kinase
    Clinical Cancer Research, 2002
    Co-Authors: Fatih M Uckun, Yaguo Zheng, Marina Cetkoviccvrlje, Alexei O Vassilev, Elizabeth Lisowski, Barbara Waurzyniak, Hao Chen, Randy Carpenter, Chunlin Chen
    Abstract:

    The purpose of the present study was to examine the in vivo pharmacokinetics and activity of alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)propenamide (LFM-A13), a novel Antileukemic Agent targeting Bruton's tyrosine kinase (BTK). We have applied an analytical high-performance liquid chromatography method for the quantitative detection of LFM-A13 in plasma samples. Our findings indicate that LFM-A13 is quickly absorbed, with the time required to reach the maximum plasma drug concentration (t(max)) being 10-18 min after i.p. administration with nearly complete bioavailability. LFM-A13 had an elimination half-life of 17-32 min after i.p. administration at dose levels of 10-50 mg/kg. LFM-A13 exhibited a dose-dependent and significant increase in the values of normalized area under the curve and maximum concentration (C(max)) as well as a dose-dependent and significant decrease in clearance values, suggesting a saturable clearance mechanism. LFM-A13 was not toxic to mice when administered systemically at dose levels ranging from 10 to 80 mg/kg. Highly effective BTK-inhibitory and apoptosis-promoting plasma concentrations of LFM-A13 could be achieved in mice without toxicity. LFM-A13 exhibited a favorable pharmacokinetic behavior that was not adversely affected by the standard chemotherapy drugs vincristine, methylprednisolone, or L-asparaginase (when used as combination treatment, VPL) and significantly improved the chemotherapy response and survival outcome of mice challenged with BCL-1 leukemia cells. Whereas only 14% of mice treated with the standard triple-drug combination VPL became long-term survivors, 41% of mice treated with this combination plus LFM-A13 survived long-term. LFM-A13 prolonged the median survival time of VPL-treated mice from 37 to 58 days. Our results confirm and extend previous studies regarding the role of BTK chemotherapy resistance of B-lineage leukemic cells (S. Mahajan et al., J. Biol. Chem., 274: 9587-9599, 1999). BTK inhibitors such as LFM-A13 may be useful as a new class of chemosensitizing and apoptosis-promoting Antileukemic Agents for treatment of patients with chemotherapy-resistant B-lineage leukemias or lymphomas.

  • bis 4 7 dimethyl 1 10 phenanthroline sulfatooxovanadium iv as a novel Antileukemic Agent with matrix metalloproteinase inhibitory activity
    Clinical Cancer Research, 2001
    Co-Authors: Rama K Narla, Yanhong Dong, Dan Klis, Fatih M Uckun
    Abstract:

    We have examined the in vitro anticancer activity of METVAN [bis(4,7-dimethyl-1,10 phenanthroline) sulfatooxovanadium(IV); VO(SO 4 )(Me 2 -Phen) 2 ] against acute lymphoblastic leukemia (ALL; NALM-6 and MOLT-3), acute myeloid leukemia (AML; HL-60), Hodgkin’s disease (HS445), and multiple myeloma (ARH-77, U266BL, and HS-SULTAN) cell lines as well as primary leukemic cells from patients with ALL, AML, and chronic acute myeloid leukemia (CML). METVAN induced apoptosis in NALM-6, MOLT-3, and HL-60 cells in a concentration-dependent fashion with EC 50 values of 0.19 ± 0.03 μm, 0.19 ± 0.01 μm, and 1.1 ± 0.2 μm, respectively. METVAN induced apoptosis at low micromolar concentrations in primary leukemic cells from patients with ALL, AML, and CML. METVAN inhibited the constitutive expression of matrix metalloproteinase (MMP)-9 protein and its gelatinolytic activity in HL-60 cells and MMP-2 as well as MMP-9 gelatinolytic activities in leukemic cells from ALL, AML, and CML patients. Furthermore, METVAN inhibited the leukemic cell adhesion to the extracellular matrix proteins laminin, type IV collagen, vitronectin, and fibronectin and the invasion through Matrigel matrix. Further preclinical development of METVAN may provide the basis for the development of more effective chemotherapy programs.

Hartmut Dohner - One of the best experts on this subject based on the ideXlab platform.

  • a randomized phase ii study on the effects of 5 aza 2 deoxycytidine combined with either amsacrine or idarubicin in patients with relapsed acute leukemia an eortc leukemia cooperative group phase ii study 06893
    Leukemia, 1997
    Co-Authors: R Willemze, Stefan Suciu, Petra Muus, E Archimbaud, Pierre Stryckmans, E A Louwagie, Zwi N Berneman, M Tjean, P W Wijermans, Hartmut Dohner
    Abstract:

    5-Aza-2'-deoxycytidine combined with either amsacrine or idarubicin has been applied in a treatment protocol for patients with a relapse of acute myeloid or lymphocytic leukemia. Sixty-three patients received 5-Aza-2'-deoxycytidine 125 mg/m 2 as a 6 h infusion every 12 h for 6 days in combination with either amsacrine 120 mg/m 2 as a 1 h infusion on days 6 and 7 (n = 30) or idarubicin 12 mg/m 2 as a 15 min infusion on days 5, 6 and 7 (n = 33). Twenty-three patients (36.5%) obtained a complete remission (CR); eight of 30 patients treated with amsacrine and 15 of 33 treated with idarubicin. Patients with an interval of more than 1 year between initial diagnosis and start of the protocol achieved CR in 51.4%, compared to 15.4% for patients with an interval of less than 1 year. Patients with normal cytogenetics had a higher CR rate (61%) than those with abnormal cytogenetic findings (15.8%). Digestive tract and hematologic toxicity was prolonged, compared to standard induction schedules. Median disease-free survival was approximately 8 months, with only 20% of patients staying in remission for more than 1 year. 5-Aza-2'-deoxycytidine is a good Antileukemic Agent with considerable toxicity. Current results merit further investigations in previously untreated leukemia.

William E. Evans - One of the best experts on this subject based on the ideXlab platform.

  • A novel protein complex distinct from mismatch repair binds thioguanylated
    PubMed, 2016
    Co-Authors: Eugene Y. Krynetski, Natalia F. Krynetskaia, Amy E. Gallo, Gopal K. Murti, William E. Evans
    Abstract:

    To elucidate molecular mechanism(s) of cellular response to mercaptopurine, a widely used Antileukemic Agent, we as-sessed mercaptopurine (MP) sensitivity in mismatch repair (MMR) proficient and MMR deficient human acute lymphoblas-tic leukemia (ALL) cells. Sensitivity to thiopurine cytotoxicity was not dependent on MMR (i.e., MutSa) competence among six cell lines tested. Using electrophoretic mobility shift assay analysis, we found that the incubation of nuclear extracts from ALL cells with synthetic 34-mer DNA duplexes containing de-oxythioguanosine (GS) within either GSzT or GSzC pairs, resulted in formation of a DNA-protein complex distinct from the DNA-MutSa complex and unaffected by ATP. Isolation and se-quence analysis of proteins involved in this DNA-protein com-plex identified glyceraldehyde 3-phosphate dehydrogenas

  • a novel protein complex distinct from mismatch repair binds thioguanylated dna
    Molecular Pharmacology, 2001
    Co-Authors: Eugene Y. Krynetski, Natalia F. Krynetskaia, Gopal K. Murti, Amy Gallo, William E. Evans
    Abstract:

    To elucidate molecular mechanism(s) of cellular response to mercaptopurine, a widely used Antileukemic Agent, we assessed mercaptopurine (MP) sensitivity in mismatch repair (MMR) proficient and MMR deficient human acute lymphoblastic leukemia (ALL) cells. Sensitivity to thiopurine cytotoxicity was not dependent on MMR (i.e., MutSa) competence among six cell lines tested. Using electrophoretic mobility shift assay analysis, we found that the incubation of nuclear extracts from ALL cells with synthetic 34-mer DNA duplexes containing deoxythioguanosine (G S ) within either G S z To r G S zC pairs, resulted in formation of a DNA-protein complex distinct from the DNAMutSa complex and unaffected by ATP. Isolation and sequence analysis of proteins involved in this DNA-protein complex identified glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as a component. Western blot analysis of nuclear extracts from a panel of human lymphoblastic leukemia cell lines revealed markedly different basal levels of GAPDH in nuclei, which was significantly related to thiopurine sensitivity (p 5 0.001). Confocal analysis revealed markedly different intracellular distribution of GAPDH between nucleus and cytosol in six human ALL cell lines. Redistribution of GAPDH from cytosol to nucleus was evident after MP treatment. These findings indicate that a new DNA-protein complex containing GAPDH and distinct from known MMR protein-DNA complexes binds directly to thioguanylated DNA, suggesting that this may act as a sensor of structural alterations in DNA and serve as an interface between these DNA modifications and apoptosis.

R Willemze - One of the best experts on this subject based on the ideXlab platform.

  • a randomized phase ii study on the effects of 5 aza 2 deoxycytidine combined with either amsacrine or idarubicin in patients with relapsed acute leukemia an eortc leukemia cooperative group phase ii study 06893
    Leukemia, 1997
    Co-Authors: R Willemze, Stefan Suciu, Petra Muus, E Archimbaud, Pierre Stryckmans, E A Louwagie, Zwi N Berneman, M Tjean, P W Wijermans, Hartmut Dohner
    Abstract:

    5-Aza-2'-deoxycytidine combined with either amsacrine or idarubicin has been applied in a treatment protocol for patients with a relapse of acute myeloid or lymphocytic leukemia. Sixty-three patients received 5-Aza-2'-deoxycytidine 125 mg/m 2 as a 6 h infusion every 12 h for 6 days in combination with either amsacrine 120 mg/m 2 as a 1 h infusion on days 6 and 7 (n = 30) or idarubicin 12 mg/m 2 as a 15 min infusion on days 5, 6 and 7 (n = 33). Twenty-three patients (36.5%) obtained a complete remission (CR); eight of 30 patients treated with amsacrine and 15 of 33 treated with idarubicin. Patients with an interval of more than 1 year between initial diagnosis and start of the protocol achieved CR in 51.4%, compared to 15.4% for patients with an interval of less than 1 year. Patients with normal cytogenetics had a higher CR rate (61%) than those with abnormal cytogenetic findings (15.8%). Digestive tract and hematologic toxicity was prolonged, compared to standard induction schedules. Median disease-free survival was approximately 8 months, with only 20% of patients staying in remission for more than 1 year. 5-Aza-2'-deoxycytidine is a good Antileukemic Agent with considerable toxicity. Current results merit further investigations in previously untreated leukemia.