ABSTRACT
PURPOSE: This study aimed to examine the potential benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitors for patients with metabolic dysfunction-associated fatty liver disease (MAFLD) and diabetes mellitus (DM) using a real-world database. METHODS: We analyzed individuals with MAFLD and DM newly initiated on SGLT2 or dipeptidyl peptidase 4 (DPP4) inhibitors from a large-scale administrative claims database. The primary outcome was the change in the fatty liver index (FLI) assessed using a linear mixed-effects model from the initiation of SGLT2 or DPP4 inhibitors. A propensity score-matching algorithm was used to compare the change in FLI among SGLT2 and DPP4 inhibitors. RESULTS: After propensity score matching, 6547 well-balanced pairs of SGLT2 and 6547 DPP4 inhibitor users were created. SGLT2 inhibitor use was associated with a greater decline in FLI than DPP4 inhibitor use (difference at 1-year measurement, - 3.8 [95% CI - 4.7 to - 3.0]). The advantage of SGLT2 inhibitor use over DPP4 inhibitor use for improvement in FLI was consistent across subgroups. The relationship between SGLT2 inhibitors and amelioration of FLI was comparable between individual SGLT2 inhibitors. CONCLUSIONS: Our analysis using large-scale real-world data demonstrated the potential advantage of SGLT2 inhibitors over DPP4 inhibitors in patients with MAFLD and DM.
Subject(s)
Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Sodium-Glucose Transporter 2 Inhibitors , Humans , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Male , Female , Middle Aged , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/complications , Retrospective Studies , Aged , Fatty Liver/drug therapy , Adult , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/metabolismABSTRACT
Visible luminescence europium(iii) complexes with large π-conjugated systems were theoretically and experimentally studied. A strategy for extending the π-conjugation of a ligand for use with europium(iii) ions was found on the basis of fragment molecular orbital and density functional theory calculations. Using this method, a novel europium complex was designed and synthesized. Its excited state properties were assessed from the luminescence spectrum, excitation spectrum, luminescence lifetime, and luminescence quantum yield. In this study, the novel photophysics induced by the combination of visible luminescent europium(iii) ions and large π-conjugated systems are described.
ABSTRACT
A high complete remission (CR) rate has been reported in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) following imatinib-based therapy. However, the overall effect of imatinib on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is undetermined. Between 2002 and 2005, 100 newly diagnosed adult patients with Ph+ALL were registered to a phase II study of imatinib-combined chemotherapy (Japan Adult Leukemia Study Group Ph+ALL202 study) and 97 patients achieved CR. We compared clinical outcomes of 51 patients who received allo-HSCT in their first CR (imatinib cohort) with those of 122 historical control patients in the pre-imatinib era (pre-imatinib cohort). The probability of overall survival at 3 years after allo-HSCT was 65% (95% confidence interval (CI), 49-78%) for the imatinib cohort and 44% (95% CI, 35-52%) for the pre-imatinib cohort. Multivariate analysis confirmed that this difference was statistically significant (adjusted hazard ratio, 0.44, P=0.005). Favorable outcomes of the imatinib cohort were also observed for disease-free survival (P=0.007) and relapse (P=0.002), but not for non-relapse mortality (P=0.265). Imatinib-based therapy is a potentially useful strategy for newly diagnosed patients with Ph+ALL, not only providing them more chance to receive allo-HSCT, but also improving the outcome of allo-HSCT.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Fusion Proteins, bcr-abl/analysis , Hematopoietic Stem Cell Transplantation , Piperazines/administration & dosage , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Pyrimidines/administration & dosage , Adolescent , Adult , Benzamides , Cause of Death , Disease-Free Survival , Female , Graft vs Host Disease/etiology , Humans , Imatinib Mesylate , Male , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Transplantation, Homologous , Treatment OutcomeABSTRACT
We studied the effect of CMC-544, the calicheamicin-conjugated anti-CD22 monoclonal antibody, used alone and in combination with rituximab, analyzing the quantitative alteration of target molecules, that is, CD20, CD22, CD55 and CD59, in Daudi and Raji cells as well as in cells obtained from patients with B-cell malignancies (BCM). Antibody inducing direct antiproliferative and apoptotic effect, complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) were tested separately. In Daudi and Raji cells, the CDC effect of rituximab significantly increased within 12 h following incubation with CMC-544. The levels of CD22 and CD55 were significantly reduced (P<0.001 in both cells) after incubation with CMC-544, but CD20 level remained constant or increased for 12 h. Similar results were obtained in cells from 12 patients with BCM. The antiproliferative and apoptotic effect of CMC-544 were greater than that of rituximab. The ADCC of rituximab was not enhanced by CMC-544. Thus, the combination of CMC-544 and rituximab increased the in vitro cytotoxic effect in BCM cells, and sequential administration for 12 h proceeded by CMC-544 was more effective. The reduction of CD55 and the preservation of CD20 after incubation with CMC-544 support the rationale for the combined use of CMC-544 and rituximab.
Subject(s)
Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology , Lymphoma, B-Cell/immunology , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal, Humanized , Antibody-Dependent Cell Cytotoxicity/drug effects , Antineoplastic Agents/immunology , Base Sequence , Cell Line, Tumor , DNA Primers , Flow Cytometry , Humans , Inotuzumab Ozogamicin , Reverse Transcriptase Polymerase Chain Reaction , Sialic Acid Binding Ig-like Lectin 2/immunologyABSTRACT
BACKGROUND: Soluble thrombomodulin is a promising therapeutic natural anticoagulant that is comparable to antithrombin, tissue factor pathway inhibitor and activated protein C. OBJECTIVES: We conducted a multicenter, double-blind, randomized, parallel-group trial to compare the efficacy and safety of recombinant human soluble thrombomodulin (ART-123) to those of low-dose heparin for the treatment of disseminated intravascular coagulation (DIC) associated with hematologic malignancy or infection. METHODS: DIC patients (n = 234) were assigned to receive ART-123 (0.06 mg kg(-1) for 30 min, once daily) or heparin sodium (8 U kg(-1) h(-1) for 24 h) for 6 days, using a double-dummy method. The primary efficacy endpoint was DIC resolution rate. The secondary endpoints included clinical course of bleeding symptoms and mortality rate at 28 days. RESULTS: DIC was resolved in 66.1% of the ART-123 group, as compared with 49.9% of the heparin group [difference 16.2%; 95% confidence interval (CI) 3.3-29.1]. Patients in the ART-123 group also showed more marked improvement in clinical course of bleeding symptoms (P = 0.0271). The incidence of bleeding-related adverse events up to 7 days after the start of infusion was lower in the ART-123 group than in the heparin group (43.1% vs. 56.5%, P = 0.0487). CONCLUSIONS: When compared with heparin therapy, ART-123 therapy more significantly improves DIC and alleviates bleeding symptoms in DIC patients.
Subject(s)
Anticoagulants/therapeutic use , Disseminated Intravascular Coagulation/drug therapy , Thrombomodulin/therapeutic use , Aged , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Blood Coagulation/drug effects , Blood Coagulation Tests , Disseminated Intravascular Coagulation/blood , Disseminated Intravascular Coagulation/mortality , Double-Blind Method , Drug Administration Schedule , Female , Heparin/therapeutic use , Humans , Male , Middle Aged , Prospective Studies , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic use , Thrombomodulin/administration & dosage , Treatment OutcomeSubject(s)
Antineoplastic Agents/adverse effects , Gastrointestinal Stromal Tumors/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Lung Diseases, Interstitial/chemically induced , Lung Diseases, Interstitial/diagnosis , Piperazines/adverse effects , Pyrimidines/adverse effects , Aged , Aged, 80 and over , Benzamides , Diagnosis, Differential , Female , Gastrointestinal Stromal Tumors/diagnosis , Humans , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Lung Diseases, Interstitial/drug therapy , Male , Middle Aged , Risk Factors , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
To clarify the role of fragile histidine triad (FHIT) in hematological malignancies, we examined the methylation status and the expression level of the FHIT gene in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cells in comparison with the methylation of the p15(INK4B) gene. The FHIT methylation was found in 13 of 94 (13.8%) AML and 22 of 40 (55.0%) MDS cases, but not in normal mononuclear cells (MNCs). Both the frequency and density of methylation increased in the advanced-stages MDS and the relapsed AML cases. Although FHIT and p15(INK4B) methylations were not correlated in MDS and AML, increased FHIT methylation at the relapse in AML was associated with p15(INK4B) methylation. The median expression level in AML was significantly higher than in normal MNCs, although the median expression level in those with methylation was significantly lower than in those without methylation. Furthermore, the methylation level at relapse was significantly higher than at diagnosis in AML. These results suggested that FHIT methylation was accumulated through the disease progression of MDS and AML, and the role of the FHIT gene as a tumor suppressor seemed different in AML and MDS.
Subject(s)
Acid Anhydride Hydrolases/genetics , DNA Methylation , Gene Expression Regulation, Neoplastic , Leukemia, Myeloid/genetics , Myelodysplastic Syndromes/genetics , Neoplasm Proteins/genetics , Acute Disease , Azacitidine/analogs & derivatives , Azacitidine/pharmacology , Bone Marrow/pathology , Cell Cycle Proteins/genetics , Cyclin-Dependent Kinase Inhibitor p15 , Decitabine , Genes, Tumor Suppressor , Humans , Leukemia, Myeloid/etiology , Leukemia, Myeloid/pathology , Myelodysplastic Syndromes/etiology , Myelodysplastic Syndromes/pathology , RNA, Messenger/analysis , Recurrence , Tumor Suppressor Proteins/geneticsABSTRACT
Acute promyelocytic leukemia (APL) cells express a considerable level of CD33, which is a target of gemtuzumab ozogamicin (GO), and a significantly lower level of P-glycoprotein (P-gp). In this study, we examined whether GO was effective on all-trans retinoic acid (ATRA)- or arsenic trioxide (ATO)-resistant APL cells. Cells used were an APL cell line in which P-gp was undetectable (NB4), ATRA-resistant NB4 (NB4/RA), NB4 and NB4/RA that had been transfected with MDR-1 cDNA (NB4/MDR and NB4/RA/MDR, respectively), ATO-resistant NB4 (NB4/As) and blast cells from eight patients with clinically ATRA-resistant APL including two patients with ATRA- and ATO-resistant APL. The efficacy of GO was analyzed by (3)H-thymidine incorporation, the dye exclusion test and cell cycle distribution. GO suppressed the growth of NB4, NB4/RA and NB4/As cells in a dose-dependent manner. GO increased the percentage of hypodiploid cells significantly in NB4, NB4/RA and NB4/As cells, and by a limited degree in NB4/MDR and NB4/RA/MDR cells. Similar results were obtained using blast cells from the patients with APL. GO is effective against ATRA- or ATO-resistant APL cells that do not express P-gp, and the mechanism of resistance to GO is not related to the mechanism of resistance to ATRA or ATO in APL cells. Leukemia (2005) 19, 1306-1311. doi:10.1038/sj.leu.2403807; published online 26 May 2005.
Subject(s)
Aminoglycosides/pharmacology , Antibodies, Monoclonal/pharmacology , Drug Resistance, Neoplasm , Leukemia, Promyelocytic, Acute/pathology , ATP Binding Cassette Transporter, Subfamily B, Member 1/analysis , Antibodies, Monoclonal, Humanized , Arsenic Trioxide , Arsenicals/pharmacology , Cell Cycle , Cell Proliferation/drug effects , Gemtuzumab , Humans , Leukemia, Promyelocytic, Acute/drug therapy , Oxides/pharmacology , Treatment Outcome , Tretinoin/pharmacology , Tumor Cells, CulturedABSTRACT
OBJECTIVE: N-(2-hydroxyethyl)-nicotinamide nitrate (nicorandil) is a unique anti-anginal agent, reported to act as both an ATP-sensitive K(+) channel opener (PCO) and a nitric oxide donor. It also has an anti-oxidant action. We examined the effects of nicorandil on streptozotocin (STZ)-induced islet beta-cell damage both in vivo and in vitro. DESIGN AND METHODS: STZ-induced diabetic Brown Norway rats (STZ-DM) were fed with nicorandil-containing chow from day 2 (STZ-DM-N48), 3 (STZ-DM-N72), and 4 (STZ-DM-N96) to day 30. Body weight, blood glucose, and plasma insulin were measured every week. For the in vitro assay, neonatal rat islet-rich cultures were performed and cells were treated with nicorandil from 1 h before to 2 h after exposure to STZ for 30 min. Insulin secretion from islet cells was assayed after an additional 24 h of culture. We also observed the effect of nicorandil on the generation of reactive oxygen species (ROS) from rat inslinoma cells (RINm5F). RESULTS: Body weight loss and blood glucose levels of STZ-DM-N48 rats were significantly lower than those of STZ-DM rats. Immunohistochemical staining of insulin showed preservation of insulin-secreting islet beta-cells in STZ-DM-N48 rats. Nicorandil also dose-dependently recovered the insulin release from neonatal rat islet cells treated with STZ in in vitro experiments. Nicorandil did not act as a PCO on neonatal rat islet beta-cells or RINm5F cells, and did not show an inhibitory effect on poly(ADP-ribose) polymerase-1. However, the drug inhibited the production of ROS stimulated by high glucose (22.0 mmol/l) in RINm5F cells. CONCLUSIONS: These results suggested that nicorandil improves diabetes and rat islet beta-cell damage induced by STZ in vivo and in vitro. It protects islet beta-cells, at least partly, via a radical scavenging effect.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Nicorandil/pharmacology , Vasodilator Agents/pharmacology , Animals , Blood Glucose , Body Weight/drug effects , Diabetes Mellitus, Experimental/metabolism , Free Radical Scavengers/pharmacology , Glucagon/metabolism , In Vitro Techniques , Insulin/blood , Insulin/metabolism , Insulin Secretion , Male , Poly(ADP-ribose) Polymerase Inhibitors , Poly(ADP-ribose) Polymerases/metabolism , Rats , Rats, Inbred BN , Reactive Oxygen Species/metabolism , Superoxides/metabolismABSTRACT
Based on the prognostic factors obtained from our previous APL92 study, in the JALSG APL97 study, we intensified chemotherapy for patients with leukocyte counts > or = 3,000/microL and > or = 10,000/microL, also intensified consolidation chemotherapy, and then tested whether further chemotherapy is required in patients with negative RT-PCR for PML/RARalpha after the completion of consolidation therapy. Of 256 presently evaluable patients, 244 (95%) achieved CR. Predicted 5-year EFS is 67% and predicted 5-year overall survival 84%.
Subject(s)
Leukemia, Promyelocytic, Acute/drug therapy , Adult , Humans , Treatment Outcome , Tretinoin/therapeutic useABSTRACT
Point mutations of the transcription factor AML1 are associated with leukemogenesis in acute myeloblastic leukemia (AML). Internal tandem duplications (ITDs) in the juxtamembrane domain and mutations in the second tyrosine kinase domain of the Fms-like tyrosine kinase 3 (FLT3) gene represent the most frequent genetic alterations in AML. However, such mutations per se appear to be insufficient for leukemic transformation. To evaluate whether both AML1 and FLT3 mutations contribute to leukemogenesis, we analyzed mutations of these genes in AML M0 subtype in whom AML1 mutations were predominantly observed. Of 51 patients, eight showed a mutation in the Runt domain of the AML1 gene: one heterozygous missense mutation with normal function, five heterozygous frameshift mutations and two biallelic nonsense or frameshift mutations, resulting in haploinsufficiency or complete loss of the AML1 activities. On the other hand, a total of 10 of 49 patients examined had the FLT3 mutation. We detected the FLT3 mutation in five of eight (63%) patients with AML1 mutation, whereas five of 41 (12%) without AML1 mutation showed the FLT3 mutation (P=0.0055). These observations suggest that reduced AML1 activities predispose cells to the acquisition of the activating FLT3 mutation as a secondary event leading to full transformation in AML M0.
Subject(s)
DNA-Binding Proteins/genetics , Frameshift Mutation , Leukemia, Myeloid, Acute/genetics , Neoplasm Proteins , Proto-Oncogene Proteins/genetics , Receptor Protein-Tyrosine Kinases/genetics , Transcription Factors/genetics , Cell Transformation, Neoplastic/genetics , Core Binding Factor Alpha 2 Subunit , Gene Expression Regulation, Leukemic , Humans , Polymorphism, Single-Stranded Conformational , Reverse Transcriptase Polymerase Chain Reaction , fms-Like Tyrosine Kinase 3ABSTRACT
Wcor15, a member of the wheat cold-responsive (Cor) gene family, has been isolated and characterized. The deduced polypeptide WCOR15 (MW=14.7 kDa) showed high homology to the previously identified wheat and barley COR proteins. Southern blot analysis using diploid, tetraploid and hexaploid wheat and diploid Aegilops species showed that the wheat and related wild genomes possessed multiple copies of Wcor15 homologues. Five copies were assigned to the homologous group 2 chromosomes by nulli-tetrasomic analysis. Northern blot analysis showed that expression of Wcor15 was specifically induced by low-temperature. Homologous transcripts accumulated in leaves, and light markedly increased their steady-state levels. Bombardment-mediated transient expression analysis of a chimeric CaMV 35S::Wcor15-GFP construct showed protein-targeting to epidermal guard cell chloroplasts in excised spiderwort leaves. A promoter of Wcor15 contained at least three CRT/DRE-like sequence motifs found in Arabidopsis Cor genes and induced the reporter GUS gene expression in leaves of transgenic tobacco plants under low-temperature and light conditions. These results suggest that the functional Cor gene system involving the CRT/DRE cis-element is conserved in both monocotyledonous and dicotyledonous plants.
Subject(s)
Chloroplasts/metabolism , Heat-Shock Proteins/genetics , Plant Proteins/genetics , Triticum/genetics , Amino Acid Sequence , Cloning, Molecular , Cold Temperature , DNA, Complementary/chemistry , DNA, Complementary/genetics , DNA, Plant/chemistry , DNA, Plant/genetics , Dehydration , Gene Expression Regulation, Plant/drug effects , Gene Expression Regulation, Plant/radiation effects , Heat-Shock Proteins/metabolism , Light , Molecular Sequence Data , Plant Growth Regulators/pharmacology , Plant Leaves/genetics , Plant Leaves/metabolism , Plant Proteins/metabolism , Plants, Genetically Modified , Sequence Analysis, DNA , Sequence Homology, Amino Acid , Triticum/metabolismABSTRACT
Acute promyelocytic leukemia (APL) has become a curable disease by all-trans retinoic acid (ATRA)-based induction therapy followed by two or three courses of consolidation chemotherapy. Currently around 90% of newly diagnosed patients with APL achieve complete remission (CR) and over 70% of patients are curable. To further increase the CR and cure rates, detection and diagnosis of this disease at its early stage is very important, hopefully before the appearance of APL-associated coagulopathy. In induction therapy, concomitant chemotherapy is indispensable, except for patients with low initial leukocyte counts. Prophylactic use of intrathecal methotrexate and cytarabine should be done, particularly for patients with hyperleukocytosis. If patients relapse hematologically or even molecularly, arsenic trioxide will be the treatment of choice under careful electrocardiogram monitoring. Am80, liposomal ATRA, gemtuzumab ozogamicin or ATRA in combination with cytotoxic drugs may be used at this stage or later. Allogeneic SCT will be the treatment of choice after patients of age <50 years have relapsed, provided that they have HLA-identical family donors or DNA-identical unrelated donors.
Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Promyelocytic, Acute/therapy , Antineoplastic Agents/adverse effects , Humans , Leukemia, Promyelocytic, Acute/complications , Remission Induction/methods , Sarcoma, Myeloid/epidemiology , Sarcoma, Myeloid/etiology , Treatment Outcome , Tretinoin/adverse effects , Tretinoin/therapeutic useABSTRACT
To examine whether the percentage of myeloperoxidase (MPO)-positive blast cells is useful as a prognostic factor for acute myeloid leukemia (AML), cytochemical analysis of MPO was performed in 491 patients who were registered to the Japan Adult Leukemia Study Group-AML92 study. Patients were divided into two using the percentage of MPO-positive blast (high [>or=50%] and low (<50%)). Complete remission rates were 85.4% in the former and 64.1% in the latter (P=0.001). The overall survival (OS) and the disease-free survival (DFS) were significantly better in the high MPO group (48.3 vs 18.7% for OS, and 36.3 vs 20.1% for DFS, P<0.001, respectively). Multivariate analysis showed that both karyotype and the percentage of MPO-positive blast cells were equally important prognostic factors. The high MPO group still showed a better survival even when restricted to the intermediate chromosomal risk group or the patients with normal karyotype (P<0.001). The OS of patients with normal karyotype in the high MPO group was almost equal with that of the favorable chromosomal risk group. The percentage of MPO-positive blast cells is a simple and highly significant prognostic factor for AML patients, and especially useful to stratify patients with normal karyotype.
Subject(s)
Blast Crisis/pathology , Leukemia, Myeloid/pathology , Peroxidase/analysis , Acute Disease , Blast Crisis/diagnosis , Blast Crisis/mortality , Clinical Enzyme Tests , Female , Humans , Karyotyping , Leukemia, Myeloid/diagnosis , Leukemia, Myeloid/mortality , Male , Middle Aged , Multivariate Analysis , Prognosis , Remission Induction , Survival AnalysisSubject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/drug effects , Arsenicals/pharmacology , Drug Resistance, Neoplasm , Leukemia, Promyelocytic, Acute/pathology , Oxides/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/biosynthesis , Antineoplastic Agents/pharmacology , Arsenic Trioxide , Gene Expression Regulation/drug effects , Humans , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/metabolism , Tumor Cells, CulturedABSTRACT
The SH2 domain-containing inositol 5'-phosphatase (SHIP) is crucial in hematopoietic development. To evaluate the possible tumor suppressor role of the SHIP gene in myeloid leukemogenesis, we examined primary leukemia cells from 30 acute myeloid leukemia (AML) patients, together with eight myeloid leukemia cell lines. A somatic mutation at codon 684, replacing Val with Glu, was detected in one patient, lying within the signature motif 2, which is the phosphatase active site. The results of an in vitro inositol 5'-phosphatase assay revealed that the mutation reduced catalytic activity of SHIP. Leukemia cells with the mutation showed enhanced Akt phosphorylation following IL-3 stimulation. K562 cells transfected with the mutated SHIP-V684E cDNA showed a growth advantage even at lower serum concentrations and resistance to apoptosis induced by serum deprivation and exposure to etoposide. These results suggest a possible role of the mutated SHIP gene in the development of acute leukemia and chemotherapy resistance through the deregulation of the phosphatidylinositol-3,4,5-triphosphate (PI(3,4,5)P3)/Akt signaling pathway. This is the first report of a mutation in the SHIP gene in any given human cancer, and indicates the need for more attention to be paid to this gene with respect to cancer pathogenesis.
Subject(s)
Genes, Dominant/genetics , Leukemia, Myeloid/genetics , Mutation , Phosphoric Monoester Hydrolases/genetics , Acute Disease , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , COS Cells , Case-Control Studies , Chlorocebus aethiops , Drug Resistance, Neoplasm , Etoposide/pharmacology , Humans , In Vitro Techniques , Interleukin-3/metabolism , Leukemia, Myeloid/metabolism , Leukemia, Myeloid/pathology , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases , Phosphoric Monoester Hydrolases/metabolism , Phosphorylation , Transfection , Tumor Cells, Cultured , src Homology Domains/geneticsABSTRACT
Nonsteroidal antiinflammatory drugs (NSAIDs) such as indomethacin decrease mucosal PGE(2) production by inhibiting cyclooxygenase (COX) activity and produce damage in the small intestine. The development of intestinal lesions as induced by indomethacin was accompanied by increases in intestinal motility, enterobacterial invasion, and myeloperoxidase (MPO) as well as inducible nitric oxide synthase (iNOS) activity, together with the up-regulation of COX-2 and iNOS mRNA expression. Neither the selective COX-1 inhibitor, SC-560, nor the selective COX-2 inhibitor, rofecoxib, alone caused intestinal damage, but their combined administration produced lesions. SC-560, but not rofecoxib, caused intestinal hypermotility, bacterial invasion and the expression of COX-2 as well as iNOS mRNAs, yet the iNOS and MPO activity was increased only when rofecoxib was administered together with SC-560. Although SC-560 inhibited the PG production, the level of PGE(2) was recovered, in a rofecoxib-dependent manner. The intestinal hypermotility response to indomethacin was prevented by both 16,16-dimethyl PGE(2) and atropine but not ampicillin, yet all these agents inhibited not only the bacterial invasion but also the expression of COX-2 as well as the iNOS activity in the intestinal mucosa following indomethacin treatment, resulting in preventing the intestinal lesions. These results suggest that inhibition of COX-1, despite causing intestinal hypermotility, bacterial invasion and iNOS expression, up-regulates the expression of COX-2, and the PGE(2) derived from COX-2 counteracts deleterious events caused by COX-1 inhibition and maintains the mucosal integrity. These sequences of events explain why intestinal damage occurs when both COX-1 and COX-2 are inhibited.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Cyclooxygenase Inhibitors/adverse effects , Intestine, Small/enzymology , Intestine, Small/pathology , Prostaglandin-Endoperoxide Synthases/metabolism , Animals , Humans , Intestine, Small/drug effectsABSTRACT
In order to improve the disappointing prognosis of adult patients with acute lymphoblastic leukemia (ALL), we applied similar induction therapy as that used for acute myeloid leukemia (AML), ie frequent administration of doxorubicin (DOX). DOX 30 mg/m(2) was administered from days 1 to 3 and from days 8 to 10 together with vincristine, prednisolone, cyclophosphamide and L-asparaginase, followed by three courses of consolidation and four courses of intensification. From December 1993 to February 1997, 285 untreated adult patients with de novo ALL were entered. Of 263 evaluable patients (age 15 to 59; median 31), 205 (78%) obtained complete remission (CR). At a median follow-up period of 63 months, the predicted 6-year overall survival (OS) rate of all patients was 33%, and disease-free survival (DFS) rate of CR patients was 30%, respectively. By multivariate analysis, favorable prognostic factors for the achievement of CR were age <40 and WBC <50 000/microl; for longer OS were age <30 and WBC <30 000/microl; and for longer DFS of CR patients were FAB L1 and ALT <50 IU/l. Among 229 patients who had adequate cytogenetic data, 51 (22%) had Philadelphia (Ph) chromosome. Ph-negative chromosome was a common favorable prognostic factor for CR, longer OS and DFS. DFS was not different between early sequential intensification (n = 48) and intermittent intensification (n = 43) during the maintenance phase. Among CR patients under 40 years old, the 6-year survival was not different between the allocated related allo-BMT group (34 patients) and the allocated chemotherapy group (108 patients). However, among patients with Ph-positive ALL, the survival of patients who actually received allo-BMT was superior to that of patients who received chemotherapy (P = 0.046).
Subject(s)
Antibiotics, Antineoplastic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bone Marrow Transplantation , Doxorubicin/administration & dosage , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Asparaginase/administration & dosage , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Humans , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Prednisolone/administration & dosage , Prognosis , Remission Induction , Survival Analysis , Transplantation, Homologous , Vincristine/administration & dosageABSTRACT
In dogs effects of phenobarbital (PB) on hepatic cytochrome P450 (CYP) activities and on concentrations of plasma alpha 1-acid glycoprotein (AGP) were examined. Total body clearance (Cl(B)) of antipyrine and plasma AGP concentrations were monitored during oral PB treatment at a therapeutic dose for 35 days. Cl(B) of antipyrine, which reflects hepatic CYP activities, gradually increased and was maintained at about threefold concentrations compared with that before treatment, suggesting that PB induced CYP activities at a large extent even in a therapeutic dose, necessary for an antiepileptic effect. Plasma AGP concentrations also increased significantly (about fourfold). Dogs were killed at the 35th day of the PB treatment, and hepatic CYP content and enzyme kinetics of several CYPs were determined using liver microsomes. CYP content was about twofold higher than that from untreated dogs. The V(max) values for CYP1A-like activity (ethoxyresorufin O-deethylation), 2B-like activity (ethoxycoumarin O-deethylation), 2C-like activity (tolbutamide hydroxylation) and 3A-like activity (midazolam 4-hydroxylation) were higher (2-4-fold) than that in untreated dogs. In summary, a therapeutic dose of PB for antiepileptic therapy significantly induced hepatic CYPs and plasma AGP in dogs. Therefore, during antiepileptic therapy with PB, special attention must be paid to the pharmacokinetics of drugs simultaneously administered.