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1.
Ann Oncol ; 27(3): 519-25, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26759276

ABSTRACT

BACKGROUND: Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, is used to treat solid tumors and tuberous sclerosis complex (TSC). Stomatitis, an inflammation of the mucous membranes of the mouth, is a common adverse event associated with mTOR inhibitors, including everolimus. We conducted a meta-analysis of data from seven randomized, double-blind phase 3 clinical trials of everolimus to determine the clinical impact of stomatitis on efficacy and safety. PATIENTS AND METHODS: Data were pooled from the safety sets of solid tumor [breast cancer (BOLERO-2 and BOLERO-3), renal cell carcinoma (RECORD-1), carcinoid tumors (RADIANT-2), and pancreatic neuroendocrine tumors (RADIANT-3)] and TSC studies (EXIST-1 and EXIST-2). Data from solid tumor trials and TSC trials were analyzed separately. RESULTS: The rate of stomatitis was 67% in the solid tumor trials (973/1455 patients) and 70% in the TSC trials (110/157 patients). Most stomatitis events were grade 1/2, with grade 3/4 events reported in only 9% (solid tumor trials) and 8% (TSC trials) of patients. Low TSC patient numbers prevented an in-depth evaluation of stomatitis and response. In the solid tumor trials, most first stomatitis episodes (89%; n = 870) were observed within 8 weeks of starting everolimus. Patients with stomatitis occurring within 8 weeks of everolimus initiation had longer progression-free survival (PFS) than everolimus-treated patients without stomatitis in BOLERO-2 {8.5 versus 6.9 months, respectively; hazard ratio (HR), 0.78 [95% confidence interval (CI), 0.62-1.00]} and RADIANT-3 [13.9 versus 8.3 months, respectively; HR, 0.70 (95% CI, 0.48-1.04)]. A similar trend was observed in RECORD-1 [HR, 0.90 (95% CI, 0.66-1.22)] and RADIANT-2 [HR, 0.87 (95% CI, 0.61-1.22)] but not in BOLERO-3 [HR, 1.01 (95% CI, 0.75-1.36)]. CONCLUSIONS: Stomatitis did not adversely affect PFS, supporting the administration of everolimus in accordance with standard management guidelines.


Subject(s)
Antineoplastic Agents/adverse effects , Everolimus/adverse effects , Immunosuppressive Agents/adverse effects , Mucous Membrane/pathology , Stomatitis/chemically induced , TOR Serine-Threonine Kinases/antagonists & inhibitors , Antineoplastic Agents/therapeutic use , Disease-Free Survival , Everolimus/therapeutic use , Humans , Immunosuppressive Agents/therapeutic use , Neoplasms/drug therapy , Stomatitis/epidemiology , Tuberous Sclerosis/drug therapy
2.
Ann Oncol ; 26(7): 1378-84, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25851632

ABSTRACT

BACKGROUND: The open-label, phase II RECORD-2 trial compared efficacy and safety of first-line everolimus plus bevacizumab (EVE/BEV) with interferon plus bevacizumab (IFN/BEV) in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: Previously untreated patients were randomized 1:1 to bevacizumab 10 mg/kg every 2 weeks with either everolimus 10 mg/day (EVE/BEV) or interferon (9 MIU 3 times/week, if tolerated) (IFN/BEV). Tumor assessments occurred every 12 weeks. The primary objective was the assessment of treatment effect on progression-free survival (PFS), based on an estimate of the chance of a subsequent phase III trial success (50% threshold for phase II success). RESULTS: Baseline characteristics were balanced between the EVE/BEV (n = 182) and IFN/BEV (n = 183) arms. The median PFS was 9.3 and 10.0 months in the EVE/BEV and IFN/BEV arms, respectively (P = 0.485). The predicted probability of phase III success was 5.05% (hazard ratio = 0.91; 95% confidence interval 0.69-1.19). The median duration of exposure was 8.5 and 8.3 months for EVE/BEV and IFN/BEV, respectively. The percentage of patients discontinuing because of adverse events (AEs) was 23.4% for EVE/BEV and 26.9% for IFN/BEV. Common grade 3/4 AEs included proteinuria (24.4%), stomatitis (10.6%), and anemia (10.6%) for EVE/BEV and fatigue (17.1%), asthenia (14.4%), and proteinuria (10.5%) for IFN/BEV. The median overall survival was 27.1 months in both arms. CONCLUSIONS: The efficacy of EVE/BEV and IFN/BEV appears similar. No new or unexpected safety findings were identified and, with the exception of proteinuria in about one-fourth of the population, EVE/BEV was generally well tolerated. CLINICAL TRIAL REGISTRY AND TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT00719264.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Papillary/drug therapy , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Bevacizumab/administration & dosage , Carcinoma, Papillary/mortality , Carcinoma, Papillary/secondary , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/secondary , Everolimus/administration & dosage , Female , Follow-Up Studies , Humans , Interferon-alpha/administration & dosage , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Prognosis , Survival Rate , Young Adult
3.
Br J Cancer ; 106(9): 1475-80, 2012 Apr 24.
Article in English | MEDLINE | ID: mdl-22441644

ABSTRACT

BACKGROUND: A relevant percentage of patients with metastatic renal cell carcinoma develop intolerance to vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFr-TKIs) and require careful selection of subsequent treatment. This retrospective analysis evaluated the safety and efficacy of everolimus in patients enrolled in the phase-III RECORD-1 trial who discontinued previous VEGFr-TKI therapy because of toxicity. METHODS: Patients with an adverse event (AE) as their primary reason for discontinuation of previous VEGFr-TKI therapy were included. Median progression-free survival (PFS) for VEGFr-TKI-intolerant patients in each arm was estimated using the Kaplan-Meier method, and effect on PFS (hazard ratio (HR)) was calculated using the Cox proportional hazard model. RESULTS: In VEGFr-TKI-intolerant patients (n=58, 14%), median PFS was 5.4 months with everolimus and 1.9 months with placebo (HR: 0.32; P=0.004). In sunitinib-intolerant patients (n=26), median PFS was 5.1 months with everolimus and 2.8 months with placebo (HR: 0.28; P=0.033). Grade 3/4 AEs reported with everolimus in VEGFr-TKI-intolerant patients included infections (16%), fatigue (7%) and stomatitis (4%). The toxicity profile of everolimus was similar in the VEGFr-TKI-intolerant and overall study populations. CONCLUSION: Everolimus is well tolerated and efficacious with no increased toxicity in patients intolerant to VEGFr-TKI therapy.


Subject(s)
Carcinoma, Renal Cell/drug therapy , Immunosuppressive Agents/therapeutic use , Kidney Neoplasms/drug therapy , Protein Kinase Inhibitors/adverse effects , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Salvage Therapy , Sirolimus/analogs & derivatives , Adult , Aged , Aged, 80 and over , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/secondary , Double-Blind Method , Everolimus , Female , Humans , International Agencies , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Lymphatic Metastasis , Male , Middle Aged , Retrospective Studies , Sirolimus/therapeutic use , Survival Rate , Treatment Outcome
4.
Ann Oncol ; 23(9): 2399-2408, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22357447

ABSTRACT

BACKGROUND: This phase I dose-escalation study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics (PDs), and preliminary antitumor activity of BGT226, a potent, oral dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin inhibitor. PATIENTS AND METHODS: Fifty-seven patients with advanced solid tumors received BGT226 2.5-125 mg/day three times weekly (TIW). Dose escalation was guided by an adaptive Bayesian logistic regression model with overdose control. Assessments included response per RECIST, [18F]-fluorodeoxyglucose uptake, and phosphorylated-S6 in skin and paired tumor samples. RESULTS: Three patients (125 mg cohort) had dose-limiting toxic effects (grade 3 nausea/vomiting, diarrhea). BGT226-related adverse events included nausea (68%), diarrhea (61%), vomiting (49%), and fatigue (19%). BGT226 demonstrated rapid absorption, variable systemic exposure, and a median half-life of 6-9 h. Seventeen patients (30%) had stable disease (SD) as best response. Nine patients had SD for ≥16 weeks. Thirty patients (53%) achieved stable metabolic disease as assessed by [18F]-fluorodeoxyglucose-positron emission tomography; however, no correlation between metabolic response and tumor shrinkage according to computed tomography was observed. PD changes suggested PI3K pathway inhibition but were inconsistent. CONCLUSIONS: The MTD of BGT226 was 125 mg/day TIW, and the clinically recommended dose was 100 mg/day TIW. Limited preliminary antitumor activity and inconsistent target inhibition were observed, potentially due to low systemic exposure.


Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Colonic Neoplasms/drug therapy , Imidazoles/therapeutic use , Prostatic Neoplasms/drug therapy , Quinolines/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Breast Neoplasms/diagnostic imaging , Colonic Neoplasms/diagnostic imaging , Diarrhea/chemically induced , Female , Fluorodeoxyglucose F18 , Humans , Imidazoles/adverse effects , Imidazoles/pharmacokinetics , Male , Maximum Tolerated Dose , Middle Aged , Nausea/chemically induced , Phosphoinositide-3 Kinase Inhibitors , Prostatic Neoplasms/diagnostic imaging , Quinolines/adverse effects , Quinolines/pharmacokinetics , Radionuclide Imaging , Radiopharmaceuticals , TOR Serine-Threonine Kinases/antagonists & inhibitors , Treatment Outcome , Young Adult
5.
Eur J Cancer ; 48(3): 333-9, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22209391

ABSTRACT

INTRODUCTION: In the phase III RECORD-1 trial (ClinicalTrials.gov: NCT00410124), patients with metastatic renal cell carcinoma (mRCC) who progressed on previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy were randomised 2:1 to everolimus 10mg once daily (n=277) or placebo (n=139). Median progression-free survival (PFS) was 4.9months with everolimus and 1.9months with placebo (hazard ratio [HR], 0.33; P<.001). This preplanned, prospective sub-analysis evaluated PFS benefit of everolimus versus placebo in patients who had previously received 1 or 2 VEGFr-TKIs. PATIENTS AND METHODS: Median PFS was estimated using the Kaplan-Meier method, and Cox proportional hazards model was used to analyse differences in PFS. RESULTS: All patients (100%) received ⩾1 previous VEGFr-TKI; 26% of patients received 2 previous VEGFr-TKIs. Among patients who received 1 previous VEGFr-TKI, median PFS was 5.4months with everolimus and 1.9months with placebo (HR, 0.32; 95%confidence interval [CI], 0.24-0.43; P<.001). Among patients who received 2 previous VEGFr-TKIs, median PFS was 4.0months with everolimus and 1.8months with placebo (HR, 0.32; 95%CI, 0.19-0.54; P<.001). The everolimus safety profile was similar for both groups. CONCLUSIONS: Everolimus was associated with prolonged PFS relative to placebo in patients who received 1 or 2 previous VEGFr-TKIs. Patients who received only 1 previous VEGFr-TKI had apparently longer PFS with everolimus in reference to those who received 2 previous VEGFr-TKIs. These results support the use of everolimus as the standard of care in patients who fail initial VEGFr-TKI therapy.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Immunosuppressive Agents/therapeutic use , Kidney Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Sirolimus/analogs & derivatives , Adult , Antineoplastic Agents/adverse effects , Carcinoma, Renal Cell/secondary , Disease-Free Survival , Double-Blind Method , Everolimus , Female , Humans , Immunosuppressive Agents/adverse effects , Kaplan-Meier Estimate , Male , Proportional Hazards Models , Prospective Studies , Sirolimus/adverse effects , Sirolimus/therapeutic use , Young Adult
6.
J Clin Oncol ; 23(22): 4856-65, 2005 Aug 01.
Article in English | MEDLINE | ID: mdl-15939923

ABSTRACT

PURPOSE: To demonstrate that adding irinotecan to a standard weekly schedule of high-dose, infusional fluorouracil (FU) and leucovorin (folinic acid [FA]) can prolong progression-free survival (PFS). PATIENTS AND METHODS: Four hundred thirty patients with measurable or assessable metastatic colorectal cancer were randomly assigned to receive either FA 500 mg/m(2) as a 2-hour infusion and FU 2.6 g/m(2) by intravenous 24-hour infusion, both administered weekly for 6 weeks, followed by a 2-week rest (Arbeitsgemeinschaft für Internistische Onkologie [AIO] arm, n = 216), or a similar schedule but with FU 2.3 or 2.0 g/m(2) preceded by irinotecan 80 mg/m(2) administered over 30 minutes (experimental group, n = 214). RESULTS: The median PFS time in the experimental group was 8.5 months (95% CI, 7.6 to 9.9 months) compared with 6.4 months (95% CI, 5.3 to 7.2 months) in the AIO arm (P < .0001). The median overall survival time was increased from 16.9 to 20.1 months (P = .2779). The objective response rate was 62.2% (95% CI, 55.0% to 69.5%) in the experimental group and 34.4% (95% CI, 27.5% to 41.3%) in the AIO arm (P < .0001). CONCLUSION: The addition of irinotecan to the standard AIO FU/FA regimen was associated with a highly significant improvement in PFS and response rate and was well tolerated. The results of this study confirm that irinotecan in combination with high-dose infusional FU/FA is a reference first-line treatment.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Adult , Aged , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Colorectal Neoplasms/pathology , Disease Progression , Drug Administration Schedule , Female , Fluorouracil/administration & dosage , Humans , Infusions, Intravenous , Irinotecan , Leucovorin/administration & dosage , Male , Middle Aged , Survival Analysis , Treatment Outcome
7.
Eur J Cancer ; 41(3): 398-403, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15691639

ABSTRACT

UNLABELLED: Previous small phase II trials have demonstrated that the combination of 5-fluorouracil (5FU) and cisplatin(CDDP) could have clinical activity in metastatic biliary tract cancer. This randomised phase II trial was designed to assess the activity and safety of a high-dose infusional weekly 5FU alone (HDFU) and the combination of 5FU, folinic acid (FA) and CDDP. Patients were included if they had histologically proven locally advanced or metastatic biliary tract carcinoma, World Health Organisation (WHO) performance status < or = 2, bilirubin <2 x upper normal limit, adequate haematological and renal functions and had not received prior chemotherapy, even in the adjuvant setting. TREATMENTS: Arm A (HDFU) consisted of cycles of 5FU 3 g/m(2) intravenously (i.v.), 24 h infusion, weekly, for 6 weeks, followed by 1 week rest, every 7 weeks; Arm B (5FU+FA+CDDP) consisted of cycles of 5FU 2.0 g/m(2) i.v. with folinic acid 500 mg/m(2), 2 h-infusion, weekly, for 6 weeks, followed by 1 week rest plus cisplatin 50 mg/m(2), once every two weeks, for 6 weeks, followed by 1 week rest, every 7 weeks. From February 1997 to June 1999, 58 patients were randomised (29 in each arm). Patients had a median age of 58 years in Arm A and 62 years in Arm B, locally advanced disease was present in 21% of the patients in Arm A and 11% in Arm B. WHO performance status of 0/1/2 was noted in 48%/45%/7% of the patients in Arm A and 54%/43%/4% in Arm B. In both arms, the most common metastatic sites were the liver and peritoneum. Twenty-eight patients were eligible in each arm and one patient did not start the allocated therapy in Arm B. The median number of cycles was 2 [range 1-12] in Arm A and 2 [range 1-6] in Arm B. Responses for the eligible patients who started their allocated therapy were as follows: Complete Response (CR) 0% in Arm A, 4% in Arm B, Partial Response (PR) 7% in Arm A, 15% in Arm B resulting in an overall response rate [95% CI] of 7.1% in Arm A [0.9-23.5%] and 19% [6.3-38.1%] in Arm B. Disease stabilisation was observed in 46% in Arm A and 44% in Arm B. National Cancer Institute of Canada (NCIC) grade 3-4 adverse events (% of patients in Arm A/Arm B) were neutropenia 4%/26%, thrombopenia 0%/7%, stomatitis 0%/4%, vomiting 7%/14%, diarrhoea 0%/11% and neurotoxicity 4%/0%. There was one early toxic death in Arm B. The median overall survival (OS) [95% CI] was in Arm A/Arm B: 5.0 [4.0-7.4] months/8.0 [5.8-11.8] months and the median progression-free survival (PFS) was 3.3 [1.7-4.7] months/3.3 [2.3-6.7] months. Cisplatin in combination with 5FU+FA showed a higher activity than HDFU, but was more toxic. These results are not sufficient to start a phase III trial. However, our group is planning a phase III trial comparing 5FU+folinic acid versus the same schedule+oxaliplatin a platinum analogue.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biliary Tract Neoplasms/drug therapy , Cisplatin/administration & dosage , Disease Progression , Female , Fluorouracil/administration & dosage , Humans , Leucovorin/administration & dosage , Male , Middle Aged , Risk Factors , Survival Analysis , Treatment Outcome
8.
Leukemia ; 17(5): 859-68, 2003 May.
Article in English | MEDLINE | ID: mdl-12750698

ABSTRACT

This report used the framework of a large European study to investigate the outcome of patients with and without an HLA-identical sibling donor on an intention-to-treat basis. After a common remission-induction and consolidation course, patients with an HLA-identical sibling donor were scheduled for allogeneic transplantation and patients lacking a donor for autologous transplantation. In all, 159 patients alive at 8 weeks from the start of treatment were included in the present analysis. In total, 52 patients had a donor, 65 patients did not have a donor and in 42 patients the availability of a donor was not assessed. Out of 52 patients, 36 (69%) with a donor underwent allogeneic transplantation (28 in CR1). Out of 65 patients, 33 (49%) received an autograft (27 in CR1). The actuarial survival rates at 4 years were 33.3% (s.e. = 6.7%) for patients with a donor and 39.0% (s.e. = 6.5%) for patients without a donor (P = 0.18). Event-free survival rates were 23.1% (s.e. = 6.2%) and 21.5% (s.e. = 5.3%), respectively (P = 0.66). Correction for alternative donor transplants did not substantially alter the survival of the group without a donor. Also, the survival in the various cytogenetic risk groups was not significantly different when comparing the donor vs the no-donor group. This analysis shows that patients with high-risk myelodysplastic syndrome and secondary acute myeloid leukemia may benefit from both allogeneic and autologous transplantation. We were unable to demonstrate a survival advantage for patients with a donor compared to patients without a donor.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow Transplantation/methods , Leukemia, Myeloid/therapy , Myelodysplastic Syndromes/therapy , Stem Cell Transplantation , Acute Disease , Adolescent , Adult , Cytarabine/administration & dosage , Disease-Free Survival , Etoposide/administration & dosage , Female , Follow-Up Studies , Histocompatibility Testing , Humans , Idarubicin/administration & dosage , Living Donors , Male , Middle Aged , Prospective Studies , Remission Induction , Risk Factors , Transplantation Conditioning/methods , Transplantation, Autologous , Treatment Outcome
9.
Eur J Cancer ; 38 Suppl 4: S65-70, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11858968

ABSTRACT

The Gastrointestinal (GI) Tract Cancer Group's aims are to develop protocols concerning the different aspects of gastrointestinal tract malignancies, diagnosis, biology and mainly treatment. Prior to approval, new project proposals are discussed within different committees of the group and in the presence of specialists concerned, according to the type of trial. There are three main committees in the GI Group, chemotherapy, surgery and research. All projects of GI tract cancer are discussed first in the relevant committee before being discussed in the multidisciplinary plenary scientific session of the Group meeting. Multidisciplinarity has always been one of the major principles of the Group. This is well illustrated by the fact that the Chairman of the Group has been alternately a medical oncologist and a surgeon and is presently a surgeon. Radiation therapists also participate in the activity of the group. Like other EORTC groups, the GI Group has developed high standards of quality. Officers and members work in close co-operation with the staff of the Data Center in Brussels and in particular medical advisors, statisticians and data managers. Members from 32 different countries participate in the activities of the Group, mostly from European countries, but also from Russia, Egypt, Hong Kong, Israel, Peru, Russia, South Africa and many others through intergroup activities such as Australia, Canada and the USA.


Subject(s)
Gastrointestinal Neoplasms/therapy , International Agencies/organization & administration , Medical Oncology/organization & administration , Research Design , Clinical Trials as Topic/methods , Combined Modality Therapy , Europe , Humans
10.
Eur J Cancer ; 38 Suppl 4: S94-9, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11858973

ABSTRACT

The EORTC Leukemia Group comprises more than 45 qualified haematology centres in Europe. The group promotes cooperation with new centres from Central and Eastern Europe with the aim to improve the standard and quality to the level in Western Europe. Subcommittees on cytogenetics, molecular biology, and immunology, shared by experts in the field, are active and have meetings on a twice-yearly basis. The aim of our group is to organise phase II and phase III trials for patients with acute and chronic myeloid or lymphoid leukaemia, myelodysplastic syndromes and myeloma. In 2000, 330 patients have been included in nine trials of the group. Presently, more than 2600 patients included in previous and current studies are alive and under continuous follow-up allowing studies on the long-term results to be planned.


Subject(s)
Leukemia/therapy , Medical Oncology , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Europe , Humans , International Agencies/organization & administration , International Cooperation , Myelodysplastic Syndromes/therapy , Quality Assurance, Health Care
11.
Surg Oncol Clin N Am ; 10(4): 795-806, ix, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11641091

ABSTRACT

The aim of the Gastrointestinal Tract Cancer Cooperative Group is to develop protocols concerning the different aspects of gastro-intestinal tract malignancies, diagnosis, biology and treatment. All projects involving surgery are discussed first in the Surgery Committee. A multidisciplinary approach has always been one of the major principles of the group. This article provides an overview of the recent and present activities of the GI group of the EORTC in relation to surgery.


Subject(s)
Gastrointestinal Neoplasms/therapy , Catheter Ablation , Chemotherapy, Adjuvant , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/surgery , Esophageal Neoplasms/therapy , Europe , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Neoplasms/surgery , Humans , Pancreatic Neoplasms/therapy , Randomized Controlled Trials as Topic , Rectal Neoplasms/therapy , Societies, Medical , Stomach Neoplasms/therapy
12.
Biochem Med Metab Biol ; 50(1): 67-74, 1993 Aug.
Article in English | MEDLINE | ID: mdl-8373636

ABSTRACT

The activity of FAD-linked glycerophosphate dehydrogenase (m-GDH), as well as that of glutamate dehydrogenase and both glutamate-oxalacetate and glutamate-pyruvate transaminases, were measured in islet, liver, and splenocyte homogenates from 6- to 7-week-old female nonobese diabetic mice (NOD) and age- and sex-matched control mice. Despite incipient insulitis and euglycemia, the NOD mice displayed both high islet insulin content and elevated insulinemia. The activity of m-GDH, expressed relative to protein content, was not decreased in islets of NOD mice, despite the fact that such a specific activity is lower in splenic lymphocytes than islet cells. In liver homogenates, the activity of m-GDH was even higher in NOD than control mice. It is proposed, therefore, that in this model of insulin-dependent diabetes no primary decrease in islet m-GDH activity occurs, at variance with the situation recently documented in several animal models of non-insulin-dependent diabetes.


Subject(s)
Diabetes Mellitus, Type 2/metabolism , Flavin-Adenine Dinucleotide/metabolism , Glycerolphosphate Dehydrogenase/metabolism , Islets of Langerhans/enzymology , Liver/enzymology , Spleen/enzymology , Alanine Transaminase/metabolism , Animals , Aspartate Aminotransferases/metabolism , Diabetes Mellitus, Type 2/pathology , Female , Immunoassay , Insulin/blood , Islets of Langerhans/pathology , Liver/pathology , Lymphocytes/metabolism , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Spleen/pathology
13.
Biochem Mol Biol Int ; 30(3): 397-402, 1993 Jul.
Article in English | MEDLINE | ID: mdl-8401296

ABSTRACT

The activity of FAD-glycerophosphate dehydrogenase, as measured through the generation of either 3HOH from L-[2-3H]glycerol-3-phosphate in the presence of FAD or iodoformazan from iodonitrotetrazolium, displayed comparable values in islet homogenates of lean and obese (ob/ob) mice. In the liver of the obese animals, the results obtained by the colorimetric and radioisotopic assays yielded a paired ratio twice higher than in control mice. Although isoforms of the mitochondrial enzyme could be present in variable proportions depending on the cell type and genetic background, the present results suggest that, in ob/ob mice, the increased secretory responsiveness of the islet B-cell to D-glucose coincides with an unaltered activity of FAD-glycerophosphate dehydrogenase. This contrasts with the situation recently documented in db/db mice, in which an impaired secretory response of the B-cell to D-glucose is associated with a decreased activity of FAD-glycerophosphate dehydrogenase.


Subject(s)
Carbohydrate Dehydrogenases/analysis , Islets of Langerhans/enzymology , Mitochondria, Liver/enzymology , Mitochondria/enzymology , Obesity/enzymology , Alanine Transaminase/analysis , Animals , Aspartate Aminotransferases/analysis , Blood Glucose/analysis , Female , Glutamate Dehydrogenase/analysis , Insulin/analysis , Male , Mice , Mice, Inbred C57BL/metabolism , Mice, Obese/metabolism , Obesity/genetics
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