piperidines and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

piperidines has been researched along with Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma* in 17 studies

Reviews

2 review(s) available for piperidines and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

ArticleYear
Rationale for targeting the pre-B-cell receptor signaling pathway in acute lymphoblastic leukemia.
    Blood, 2015, Jun-11, Volume: 125, Issue:24

    Inhibitors of B-cell receptor (BCR) and pre-BCR signaling were successfully introduced into patient care for various subtypes of mature B-cell lymphoma (e.g., ibrutinib, idelalisib). Acute lymphoblastic leukemia (ALL) typically originates from pre-B cells that critically depend on survival signals emanating from a functional pre-BCR. However, whether patients with ALL benefit from treatment with (pre-) BCR inhibitors has not been explored. Recent data suggest that the pre-BCR functions as tumor suppressor in the majority of cases of human ALL. However, a distinct subset of human ALL is selectively sensitive to pre-BCR antagonists.

    Topics: Adenine; DNA-Binding Proteins; Humans; Molecular Targeted Therapy; Piperidines; Pre-B Cell Receptors; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cells, B-Lymphoid; Proto-Oncogene Proteins c-bcl-6; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Signal Transduction; STAT5 Transcription Factor

2015
Developing interventions for cancer-related cognitive dysfunction in childhood cancer survivors.
    Journal of the National Cancer Institute, 2014, Volume: 106, Issue:8

    Survivors of childhood cancer frequently experience cancer-related cognitive dysfunction, commonly months to years after treatment for pediatric brain tumors, acute lymphoblastic leukemia (ALL), or tumors involving the head and neck. Risk factors for cancer-related cognitive dysfunction include young age at diagnosis, treatment with cranial irradiation, use of parenteral or intrathecal methotrexate, female sex, and pre-existing comorbidities. Limiting use and reducing doses and volume of cranial irradiation while intensifying chemotherapy have improved survival and reduced the severity of cognitive dysfunction, especially in leukemia. Nonetheless, problems in core functional domains of attention, processing speed, working memory and visual-motor integration continue to compromise quality of life and performance. We review the epidemiology, pathophysiology and assessment of cancer-related cognitive dysfunction, the impact of treatment changes for prevention, and the broad strategies for educational and pharmacological interventions to remediate established cognitive dysfunction following childhood cancer. The increased years of life saved after childhood cancer warrants continued study toward the prevention and remediation of cancer-related cognitive dysfunction, using uniform assessments anchored in functional outcomes.

    Topics: Adolescent; Adult; Age Factors; Antimetabolites, Antineoplastic; Attention; Benzhydryl Compounds; Brain Neoplasms; Central Nervous System Stimulants; Child; Child, Preschool; Cognitive Dysfunction; Comorbidity; Cranial Irradiation; Donepezil; Early Intervention, Educational; Education, Special; Head and Neck Neoplasms; Human Growth Hormone; Humans; Indans; Infant; Injections, Spinal; Memory, Short-Term; Methotrexate; Methylphenidate; Modafinil; Neoplasms; Neurosurgical Procedures; Nootropic Agents; Patient Education as Topic; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Psychomotor Performance; Quality of Life; Radiotherapy Dosage; Risk Factors; Severity of Illness Index; Sex Factors; Survivors; Thinking; Wakefulness-Promoting Agents; Young Adult

2014

Trials

2 trial(s) available for piperidines and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

ArticleYear
BTK inhibition sensitizes acute lymphoblastic leukemia to asparaginase by suppressing the amino acid response pathway.
    Blood, 2021, 12-09, Volume: 138, Issue:23

    Asparaginase (ASNase) therapy has been a mainstay of acute lymphoblastic leukemia (ALL) protocols for decades and shows promise in the treatment of a variety of other cancers. To improve the efficacy of ASNase treatment, we used a CRISPR/Cas9-based screen to identify actionable signaling intermediates that improve the response to ASNase. Both genetic inactivation of Bruton's tyrosine kinase (BTK) and pharmacological inhibition by the BTK inhibitor ibrutinib strongly synergize with ASNase by inhibiting the amino acid response pathway, a mechanism involving c-Myc-mediated suppression of GCN2 activity. This synthetic lethal interaction was observed in 90% of patient-derived xenografts, regardless of the genomic subtype. Moreover, ibrutinib substantially improved ASNase treatment response in a murine PDX model. Hence, ibrutinib may be used to enhance the clinical efficacy of ASNase in ALL. This trial was registered at www.clinicaltrials.gov as # NCT02884453.

    Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Amino Acids; Animals; Antineoplastic Agents; Apoptosis; Asparaginase; Cell Line, Tumor; Humans; Mice; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Signal Transduction

2021
Phase I and pharmacokinetic study of flavopiridol followed by 1-beta-D-arabinofuranosylcytosine and mitoxantrone in relapsed and refractory adult acute leukemias.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2005, Dec-01, Volume: 11, Issue:23

    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-beta-D-arabinofuranosylcytosine (ara-C) and mitoxantrone.. Flavopiridol was given by 1-hour infusion daily for 3 days beginning day 1 followed by 2 g/m2/72 h ara-C beginning day 6 and 40 mg/m2 mitoxantrone beginning day 9. In vivo correlates included pharmacokinetics, modulation of blast cycle regulators, and serum and marrow supernatant vascular endothelial growth factor levels.. Of 34 adults receiving induction therapy, 16 (47%) evinced direct leukemia cytotoxicity with > or =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/m2/d with profound neutropenia >40 days duration, and maximal tolerated dose was 50 mg/m2/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%).. 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/m2/d x 3 days in combination with cytotoxic and biological agents for acute leukemias.

    Topics: Adult; Aged; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Cells; Cattle; Cell Proliferation; Cohort Studies; Cytarabine; Endothelium, Vascular; Female; Flavonoids; Humans; Leukemia, Myeloid, Acute; Male; Maximum Tolerated Dose; Middle Aged; Mitoxantrone; Neoplasm Recurrence, Local; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Salvage Therapy; U937 Cells; Vascular Endothelial Growth Factor A

2005

Other Studies

13 other study(ies) available for piperidines and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

ArticleYear
A rohitukine derivative IIIM-290 induces p53 dependent mitochondrial apoptosis in acute lymphoblastic leukemia cells.
    Molecular carcinogenesis, 2021, Volume: 60, Issue:10

    Rohitukine, a chromone alkaloid extracted from Dysoxylum binectariferum, has a propitious anticancer activity. Our previous study shows that a new Rohitukine derivative IIIM-290 restricts the growth of pancreatic cancer in vivo and in vitro. In the present findings, we report the mechanism of cell death induced by IIIM-290 in MOLT-4 cells (acute lymphoblastic leukemia) and its anticancer potential against various murine leukemic tumor models in vivo. We found that IIIM-290 induced apoptosis through upregulation of different apoptotic proteins like PUMA, BAX, cytochrome c, cleaved (active) caspase-3, and cleaved PARP in MOLT-4 cells. Moreover, IIIM-290 abated mitochondrial membrane potential, elevated calcium levels, reactive oxygen species, and arrested growth of MOLT-4 cells in the synthesis (S) phase of the cell cycle. Interestingly, the elevation in proapoptotic markers was p53 dependent-the silencing of p53 abrogated apoptosis (programmed cell death) triggered by IIIM-290 in MOLT-4 cells. Furthermore, IIIM-290 significantly enhanced the survival of animals with P388 and L1210 leukemia. Thus, our results put IIIM-290 as a potential candidate for the anticancer lead.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Cell Line, Tumor; Chromones; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Mice; Mitochondria; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

2021
The Bruton's tyrosine kinase inhibitor ibrutinib abrogates bispecific antibody-mediated T-cell cytotoxicity.
    British journal of haematology, 2020, Volume: 189, Issue:1

    Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antibodies, Bispecific; Antineoplastic Agents, Immunological; Cell Line, Tumor; Humans; Immunity, Cellular; Neoplasm Proteins; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; T-Lymphocytes

2020
Failure of tofacitinib to achieve an objective response in a
    Cold Spring Harbor molecular case studies, 2020, Volume: 6, Issue:4

    T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia (T-LBL/T ALL) is an aggressive hematological malignancy arising from malignant transformation of T-cell progenitors with poor prognosis in adult patients. Outcomes are particularly dismal in the relapsed/refractory setting, and therapeutic options are limited in this context. Genomic profiling has shown frequent aberrations in the JAK-STAT pathway, including recurrent mutations in

    Topics: Aged; Cell Transformation, Neoplastic; DEAD-box RNA Helicases; Drug Resistance, Neoplasm; Exome Sequencing; Female; Humans; Janus Kinase 1; Janus Kinase 3; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidines; Transcription Factors

2020
Ibrutinib improves the development of acute lymphoblastic leukemia by activating endoplasmic reticulum stress-induced cell death.
    Die Pharmazie, 2018, 05-01, Volume: 73, Issue:5

    The current study mainly aims to evaluate the effects of ibrutinib on endoplasmic reticulum stress (ERS)-induced apoptosis in Reh cells, which may shed light on the treatment of acute lymphoblastic leukemia (ALL) among children. In line with previous studies, our data show that ibrutinib significantly suppressed Reh cell viability in a time- and dose-dependent manner. We further evaluated the role of ibrutinib on Reh cell colony formation and apoptosis. Ibrutinib inhibited clonogenic capacity and induced Reh cell apoptosis, suggesting an anti-tumor effects of ibrutinib in the progression of ALL. Further study showed that ibrutinib treatment increased ERS-related protein expression, including Bip, ATF4 and CHOP, suggesting the induction of ER-stress in Reh cells. More importantly, once ER-stress was suppressed by tauroursodeoxycholic acid (TUDCA), an ER-stress inhibitor, the upregulation of Bip, ATF4, CHOP, cleaved-caspase3 and cleaved-PARP after ibrutinib treatment was partially reversed, suggesting that induction of ALL cell apoptosis by ibrutinib was partially attributed to activation of ER stress. In summary, we showed novel data that ER-stress induced cell apoptosis plays a key role in the therapeutic effects of ibrutinib on ALL cell malignancies.

    Topics: Activating Transcription Factor 4; Adenine; Apoptosis; Caspase 3; Cell Line, Tumor; Cell Survival; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Heat-Shock Proteins; Humans; Piperidines; Poly (ADP-Ribose) Polymerase-1; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Taurochenodeoxycholic Acid; Transcription Factor CHOP

2018
[SDF-1α/CXCR4 Mediated Drug Resistance Can be Reversed by Ibrutinib in Acute Lymphoblastic Leukemia].
    Zhongguo shi yan xue ye xue za zhi, 2017, Volume: 25, Issue:3

    To explore the effect of Ibrutinib on the chemoresistance mediated by SDF-1α/CXCR4 axis in ALL cells.. Flow cytometry was used to detect the apoptosis of cell line and expression of surface membrane CXCR4, Western blot was used to determine the expression level of CXCR4, ERK and Bcl-xL proteins, qPCR was used to assay the mRNA level of CXCR4.. Ibrutinib enhanced the apoptosis induced by adriamycin(ADR) (17.100±4.3% to 28.133±3.16%); Ibrutinib inhibited the phosphorylation of CXCR4 induced by SDF-1α and with concentration- and time- dependent manner (r

    Topics: Adenine; Chemokine CXCL12; Drug Resistance, Neoplasm; Humans; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrazoles; Pyrimidines; Receptors, CXCR4

2017
How Does the L884P Mutation Confer Resistance to Type-II Inhibitors of JAK2 Kinase: A Comprehensive Molecular Modeling Study.
    Scientific reports, 2017, 08-22, Volume: 7, Issue:1

    Janus kinase 2 (JAK2) has been regarded as an essential target for the treatment of myeloproliferative neoplasms (MPNs). BBT594 and CHZ868, Type-II inhibitors of JAK2, illustrate satisfactory efficacy in preclinical MPNs and acute lymphoblastic leukemia (ALL) models. However, the L884P mutation of JAK2 abrogates the suppressive effects of BBT594 and CHZ868. In this study, conventional molecular dynamics (MD) simulations, umbrella sampling (US) simulations and MM/GBSA free energy calculations were employed to explore how the L884P mutation affects the binding of BBT594 and CHZ868 to JAK2 and uncover the resistance mechanism induced by the L884P mutation. The results provided by the US and MD simulations illustrate that the L884P mutation enhances the flexibility of the allosteric pocket and alters their conformations, which amplify the conformational entropy change (-TΔS) and weaken the interactions between the inhibitors and target. Additionally, the structural analyses of BBT594 and CHZ868 in complex with the WT JAK2 illustrate that the drug tail with strong electronegativity and small size located in the allosteric pocket of JAK2 may enhance anti-resistance capability. In summary, our results highlight that both of the changes of the conformational entropies and enthalpies contribute to the L884P-induced resistance in the binding of two Type-II inhibitors into JAK2 kinase.

    Topics: Allosteric Site; Aminopyridines; Benzimidazoles; Drug Resistance, Neoplasm; Entropy; Humans; Janus Kinase 2; Models, Molecular; Molecular Dynamics Simulation; Mutation; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Binding; Protein Conformation; Protein Kinase Inhibitors; Protein Structure, Secondary; Pyrimidines

2017
The NK-1 receptor is expressed in human leukemia and is involved in the antitumor action of aprepitant and other NK-1 receptor antagonists on acute lymphoblastic leukemia cell lines.
    Investigational new drugs, 2012, Volume: 30, Issue:2

    Substance P and neurokinin-1 (NK-1) receptor antagonists respectively induce cell proliferation and cell inhibition in human cancer cell lines. In acute lymphoblastic leukemia (ALL), substance P is expressed in human blast cells. However, the possible presence of NK-1 receptors in human ALL and the issue of whether the antitumor action of NK-1 receptor antagonists is exerted or not on human ALL (T-ALL BE-13 and B-ALL SD-1 cell lines) remain unknown. An immunoblot analysis was performed and an in vitro study of the cytotoxicity of three NK-1 receptor antagonists (L-733,060, L-732,138, aprepitant) was carried out on both cell lines. NK-1 receptors were found in those cell lines, and both expressed mRNA for this receptor. Using a knockdown method, we demonstrate that NK-1 receptors are involved in the viability of tumor cells. TAC1R cDNA was detected in the ALL cell lines by real-time quantitative RT-PCR. We also observed that the three NK-1 receptor antagonists elicited the inhibition of ALL cell growth; that the specific antitumor action of the NK-1 receptor antagonists occurs through the NK-1 receptor, and that ALL cell death is due to apoptosis. These findings suggest that NK-1 receptor antagonists could be considered as new antitumor drugs for the treatment of human ALL.

    Topics: Antineoplastic Agents; Apoptosis; Aprepitant; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Cell Survival; Child; Dose-Response Relationship, Drug; Female; Humans; Inhibitory Concentration 50; Morpholines; Neurokinin-1 Receptor Antagonists; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Real-Time Polymerase Chain Reaction; Receptors, Neurokinin-1; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA, Messenger; Substance P; Tryptophan

2012
Chemotherapy resistance in acute lymphoblastic leukemia requires hERG1 channels and is overcome by hERG1 blockers.
    Blood, 2011, Jan-20, Volume: 117, Issue:3

    Bone marrow mesenchymal cells (MSCs) can protect leukemic cells from chemotherapy, thus increasing their survival rate. We studied the potential molecular mechanisms underlying this effect in acute lymphoblastic leukemia (ALL) cells. Coculture of ALL cells with MSCs induced on the lymphoblast plasma membrane the expression of a signaling complex formed by hERG1 (human ether-à-go-go-related gene 1) channels, the β(1)-integrin subunit, and the chemokine receptor CXC chemokine receptor-4. The assembly of such a protein complex activated both the extracellular signal-related kinase 1/2 (ERK1/2) and the phosphoinositide 3-kinase (PI3K)/Akt prosurvival signaling pathways. At the same time, ALL cells became markedly resistant to chemotherapy-induced apoptosis. hERG1 channel function appeared to be important for both the initiation of prosurvival signals and the development of drug resistance, because specific channel blockers decreased the protective effect of MSCs. NOD/SCID mice engrafted with ALL cells and treated with channel blockers showed reduced leukemic infiltration and had higher survival rates. Moreover, hERG1 blockade enhanced the therapeutic effect produced by corticosteroids. Our findings provide a rationale for clinical testing of hERG1 blockers in the context of antileukemic therapy for patients with ALL.

    Topics: Animals; Antineoplastic Agents; Blotting, Western; Cell Membrane; Cells, Cultured; Coculture Techniques; Doxorubicin; Drug Resistance, Neoplasm; Ether-A-Go-Go Potassium Channels; Female; Humans; Integrin beta1; Mesenchymal Stem Cells; Mice; Mice, Inbred NOD; Mice, SCID; Multiprotein Complexes; Piperidines; Potassium Channel Blockers; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Pyridines; Receptors, CXCR4; RNA Interference; Signal Transduction; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

2011
Flavopiridol displays preclinical activity in acute lymphoblastic leukemia.
    Pediatric blood & cancer, 2008, Volume: 50, Issue:4

    New agents are needed for treatment of children with relapsed acute lymphoblastic leukemia (ALL). Based on altered expression of cell cycle regulatory proteins, including frequent p16 (INK4A) and p15 (INK4B) deletions, flavopiridol (FP; Alvocidib) is an attractive agent for relapsed ALL.. We evaluated the efficacy of FP in ALL cell lines using cell proliferation assays, determined the effects of FP treatment on cell growth and viability in cell lines and patient samples, examined cell cycle kinetics, and evaluated the effect of FP on endogenous cyclin-dependent kinase (CDK) activity, Mcl-1 expression, and RNA polymerase II expression and phosphorylation.. ALL cell lines are sensitive to FP. At lower concentrations, FP induces transient G(1)-S cell cycle arrest and modest levels of apoptosis in cell lines. In contrast, a sustained G(1)-S and G(2)-M arrest and substantial apoptosis are observed following exposure to higher FP concentrations. After treatment with FP, ALL cell lines have decreased expression of retinoblastoma protein phosphorylated at serines 795 and 807/811, indicating reduced CDK activity. We also show that ALL cell lines are sensitive to clinically achievable concentrations of FP in medium supplemented with human serum and that FP reduces the expression of Mcl-1 and phosphorylated forms of the C-terminal domain of RNA polymerase II. FP also increases cell death by approximately twofold over baseline in primary ALL blasts.. These data provide a biological rationale for testing FP in relapsed ALL.

    Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Cycle; Cell Line, Tumor; Flavonoids; Humans; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins; Neoplasm Recurrence, Local; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins c-bcl-2; Retinoblastoma Protein; RNA Polymerase II

2008
In vitro cytotoxicity of nelarabine, clofarabine and flavopiridol in paediatric acute lymphoblastic leukaemia.
    British journal of haematology, 2007, Volume: 137, Issue:2

    The in vitro efficacies of three new drugs--clofarabine (CLOF), nelarabine (NEL) and flavopiridol (FP) - were assessed in a panel of acute lymphoblastic leukaemia (ALL) cell lines. The 50% inhibitory concentration (IC50) for CLOF across all lines was 188-fold lower than that of NEL. B-lineage, but not T-lineage lines, were >7-fold more sensitive to CLOF than cytosine arabinoside (ARAC). NEL IC50 was 25-fold and 113-fold higher than ARAC in T- and B-lineage, respectively. T-ALL cells were eightfold more sensitive to NEL than B-lineage but there was considerable overlap. FP was more potent in vitro than glucocorticoids and thiopurines and at doses that recent phase I experience predicts will translate into clinical efficacy. Potential cross-resistance of CLOF, NEL and FP was observed with many front-line ALL therapeutics but not methotrexate or thiopurines. Methotrexate sensitivity was inversely related to that of NEL and FP. Whilst NEL was particularly effective in T-ALL, a subset of patients with B-lineage ALL might also be sensitive. CLOF appeared to be marginally more effective in B-lineage than T-ALL and has a distinct resistance profile that may prove useful in combination with other compounds. FP should be widely effective in ALL if sufficient plasma levels can be achieved clinically.

    Topics: Adenine Nucleotides; Antineoplastic Agents; Arabinonucleosides; Burkitt Lymphoma; Child; Clofarabine; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Flavonoids; Humans; Inhibitory Concentration 50; Leukemia-Lymphoma, Adult T-Cell; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tumor Cells, Cultured

2007
A farnesyltransferase inhibitor increases survival of mice with very advanced stage acute lymphoblastic leukemia/lymphoma caused by P190 Bcr/Abl.
    Leukemia, 2004, Volume: 18, Issue:1

    Treatment of chronic myelogenous leukemia with a specific inhibitor of the Bcr/Abl tyrosine kinase, imatinib, has shown great promise. However, acute lymphoblastic leukemias that express Bcr/Abl only transiently respond to imatinib. Therefore, alternative treatments for this type of leukemia are urgently needed. Here, we examined the activity of the farnesyltransferase inhibitor SCH66336 as a single chemotherapeutic agent in a nude mouse model representative of very advanced stage Bcr/Abl P190-positive lymphoblastic leukemia/lymphoma. Our results show that oral administration of the inhibitor was able to significantly increase the survival of these mice compared to controls treated with vehicle (P<0.005), and caused marked regression of the tumor burden in the treated mice. Upon prolonged treatment, lymphomas re-emerged and a subset of cells from two of such lymphomas tested was able to survive in the presence of increased concentrations of SCH66336. The same cells, however, remained sensitive towards imatinib. A combination of the two drugs, preceded by a therapy to reduce the initial tumor burden, could be very effective in the treatment of Ph-positive ALL. We conclude that SCH66336, on its own, is remarkably effective in eradicating large numbers of lymphoblastic lymphoma cells and causing visible reduction in tumor size, with minimal toxicity.

    Topics: Administration, Oral; Alkyl and Aryl Transferases; Animals; Antineoplastic Agents; Benzamides; Disease Models, Animal; Farnesyltranstransferase; Female; Fusion Proteins, bcr-abl; Imatinib Mesylate; Leukemia, Experimental; Lymphoma; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Nude; Mice, Transgenic; Piperazines; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Survival Rate; Tumor Cells, Cultured

2004
Timed sequential therapy of acute leukemia with flavopiridol: in vitro model for a phase I clinical trial.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2003, Volume: 9, Issue:1

    The survival of adults with acute leukemias remains unsatisfactory and requires new treatment approaches. Flavopiridol modulates cell cycle progression, inhibits transcription, and induces apoptosis. We designed an in vitro model of timed sequential therapy for acute leukemia to determine whether flavopiridol can: (a). trigger apoptosis in fresh acute leukemia; and (b). recruit surviving leukemic cells to a proliferative state, thereby priming such cells for the S-phase-related cytotoxicity of 1-beta-D-arabinofuranosylcytosine (ara-C).. Bone marrow cells from 20 adults with relapsed and refractory acute leukemias were enriched for blasts by Ficoll Hypaque sedimentation. Blasts were cultured on day 0 in flavopiridol 250 nM for 24 h, removed from flavopiridol for 24 h, and then cultured in ara-C 1 microM for an additional 72 h (F(250)A(1)). Apoptosis and cell cycle phase distribution were estimated from cells stained with propidium iodide. Cell survival was determined after the 72 h ara-C exposure by double cytofluorescence assay with fluorescein diacetate and propidium iodide.. Flavopiridol induced a 4.3-fold increase in apoptosis in human leukemia samples within the first 24 h of culture. Subsequent removal of flavopiridol led to a 1.7-fold increase in the proportion of cells in S phase by day 2. Mean survival in F(250)A(1) cultures after 72 h exposure to ara-C was 35.6% compared with flavopiridol alone (F(250)A(0), 56.1%; P = 0.0003) and ara-C alone (F(0)A(1), 65.2%; P < 0.00001).. Flavopiridol induces apoptosis in marrow blasts from patients with refractory acute leukemias. Furthermore, flavopiridol pretreatment increases the proapoptotic and cytotoxic effects of ara-C. The advantage of sequential FP(250)A(1) over either agent alone is seen for both acute myelogenous leukemia and acute lymphoblastic leukemia. These findings support a clinical trial of timed sequential therapy where flavopiridol is given for cytoreduction and subsequent priming of remaining leukemic cells for enhanced cycle-dependent drug cytotoxicity.

    Topics: Adult; Aged; Antineoplastic Agents; Apoptosis; Bone Marrow Cells; Cell Division; Cell Survival; Coloring Agents; Female; Flavonoids; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Propidium; S Phase; Time Factors; Tumor Cells, Cultured

2003
Treatment of Bcr/Abl-positive acute lymphoblastic leukemia in P190 transgenic mice with the farnesyl transferase inhibitor SCH66336.
    Blood, 2001, Mar-01, Volume: 97, Issue:5

    The Philadelphia (Ph) chromosome is found in approximately 3% of pediatric patients with acute lymphoblastic leukemia (ALL) and the percentage markedly increases in adult patients. The prognosis for this class of patients is poor, and no standard chemotherapy combination so far has demonstrated long-term efficacy. The Ph-translocation joins the BCR and ABL genes and leads to expression of a chimeric Bcr/Abl protein with enhanced tyrosine kinase activity. This increase in activity leads to malignant transformation by interference with basic cellular functions such as the control of proliferation, adherence to stroma and extracellular matrix, and apoptosis. One important pathway activated by Bcr/Abl is the Ras pathway. Ras proteins have to undergo a series of posttranslational modifications to become biologically active. The first modification is the farnesylation of the C-terminus catalyzed by farnesyl transferase. We studied the effect of the farnesyl transferase inhibitor SCH66336 in an in vivo murine model of Bcr/Abl-positive acute lymphoblastic leukemia. In the early leukemic phase, mice were randomly assigned to a treatment, a vehicle, and a nontreatment group. The treatment was well tolerated without any detectable side effects. All animals of the control groups died of leukemia/lymphoma within 103 days (range, 18-103 days). In contrast, 80% of the drug-receiving group survived without any signs of leukemia or lymphoma until termination of treatment, after a median treatment period of 200 days (range, 179-232 days). We conclude that farnesyl transferase inhibitor SCH66336 is able to revert early signs of leukemia and significantly prolongs survival in a murine ALL model.

    Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Agents; Bone Marrow; Farnesyltranstransferase; Genes, abl; Mice; Mice, Transgenic; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyridines; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Survival Rate

2001