Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038362 (stomatitis)
 8,852 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Constitutive activation of receptor tyrosine kinases (RTKs) is a frequent event in human cancer cells. Activating mutations in Fms-like tyrosine kinase 3 (FLT-3), notably, internal tandem duplications in the juxtamembrane domain (FLT-3 ITD), have been causally linked to acute myeloid leukemia. As we describe here, FLT-3 ITD exists predominantly in an immature, underglycosylated 130-kDa form, whereas wild-type FLT-3 is expressed predominantly as a mature, complex glycosylated 150-kDa molecule. Endogenous FLT-3 ITD, but little wild-type FLT-3, is detectable in the endoplasmic reticulum (ER) compartment. Conversely, cell surface expression of FLT-3 ITD is less efficient than that of wild-type FLT-3. Inhibition of FLT-3 ITD kinase by small molecules, inactivating point mutations, or coexpression with the protein-tyrosine phosphatases (PTPs) SHP-1, PTP1B, and PTP-PEST but not RPTPalpha promotes complex glycosylation and surface localization. However, PTP coexpression has no effect on the maturation of a surface glycoprotein of vesicular stomatitis virus. The maturation of wild-type FLT-3 is impaired by general PTP inhibition or by suppression of endogenous PTP1B. Enhanced complex formation of FLT-3 ITD with the ER-resident chaperone calnexin indicates that its retention in the ER is related to inefficient folding. The regulation of RTK maturation by tyrosine phosphorylation was observed with other RTKs as well, defines a possible role for ER-resident PTPs, and may be related to the altered signaling quality of constitutively active, transforming RTK mutants.
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PMID:Tyrosine phosphorylation regulates maturation of receptor tyrosine kinases. 1583 74

Nonviral producer cell proteins incorporated into retroviral vector surfaces profoundly influence infectivity and in vivo half-life. We report the purification and concentration of lentiviral vectors using these surface proteins as an efficient gene transduction strategy. Biotinylation of these proteins and streptavidin paramagnetic particle concentration enhances titer 400- to 2,500-fold (to 10(9) CFU/ml for vesicular stomatitis virus G protein and 5 x 10(8) for amphotropic murine leukemia virus envelope). This method also uses newly introduced membrane proteins (B7.1 and DeltaLNGFR) directed to lentiviral surfaces, allowing up to 17,000-fold concentrations. Particle conjugation of lentivirus allows facile manipulation in vitro, resulting in the transduction of 48 to 94% of human acute myeloid leukemia blasts.
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PMID:Conjugation of lentivirus to paramagnetic particles via nonviral proteins allows efficient concentration and infection of primary acute myeloid leukemia cells. 1618 21

The potential mechanism of the chemotherapy resistance in acute myeloid leukemia (AML) is the multidrug resistance (MDR-1) gene product P-glycoprotein (P-gp), which is often overexpressed in myeloblasts from acute myeloid leukemia. In a multicenter clinical trial, 38 patients with poor risk forms of AML were treated with tetrandrine (TET), a potent inhibitor of the MDR-1 efflux pump, combined with daunorubicin (DNR), etoposide and cytarabine (TET-DEC). Overall, post-chemotherapy marrow hypoplasia was achieved in 36 patients. Sixteen patients (42%) achieved complete remission or restored chronic phase, 9 achieved partial remission (PR) and 13 failed therapy. Toxicities included infection, myelosuppression, stomatitis, mucositis, cerebellar toxicity and reversible cardiotoxicity. There was no significant difference in response for P-gp-positive and -negative patients. P-gp function was assessed in 26 patients by flow cytometric analysis, TET-contained plasma-augmented DNR accumulation relative to pretreatment plasma in K562/A02 cells by a median value of 88+/-101% (range, 11-501%). However, there was no difference in DNR uptake between responding and non-responding patients. Our data showed that TET-DEC was relatively well tolerated in these patients with poor risk AML, and had encouraging antileukemic effects.
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PMID:Combination of tetrandrine as a potential-reversing agent with daunorubicin, etoposide and cytarabine for the treatment of refractory and relapsed acute myelogenous leukemia. 1621 52

The cytotoxic effect of cytarabine (Ara-C) on myeloid leukemic cells is enhanced by concomitant use of granulocyte colony-stimulating factor (G-CSF) in vitro. The feasibility of a conditioning regimen consisting of G-CSF-combined 24 g/m2 Ara-C, 90 mg/m2 fludarabine, and 12 Gy total body irradiation was studied for five patients with acute myelogenous leukemia in cord blood transplantation (CBT). Graft vs. host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. After the conditioning regimen, 2.48 x 10(7)/kg (2.28-3.53) of cord blood nucleated cells was infused. Neutrophil counts consistently >0.5 x 10(9)/L was achieved 24 d (22-32) after CBT. Grade I stomatitis and gastrointestinal toxicities occurred in all patients. Grades I and II acute GVHD occurred in one and four patients, respectively, which resolved without steroid therapy. Sepsis and aspergillosis occurred in two and one patients, respectively. All patients were alive without leukemia relapse at a follow up of 15 months (12-43) after CBT. This conditioning regimen could avoid the toxicities of high-dose cyclophosphamide but might enhance the cytotoxic effect of Ara-C. Large-scale studies will be needed to determine the efficacy and safety of the conditioning regimen in CBT.
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PMID:Cord blood transplantation for acute myelogenous leukemia using a conditioning regimen consisting of granulocyte colony-stimulating factor-combined high-dose cytarabine, fludarabine, and total body irradiation. 1657 43

Intestinal barrier function was prospectively examined in the course of a clinical trial evaluating the efficacy and safety of lisofylline for reducing cytotoxic therapy-induced intestinal epithelial damage-related infectious morbidity in patients receiving standard remission-induction therapy for acute myeloid leukaemia. The absorption and permeation of oral D-Xylose, lactulose and mannitol were measured weekly from baseline until marrow recovery in adult recipients of idarubicin plus cytarabine for untreated acute myeloid leukaemia. These studies were correlated with non-haematologic chemotherapy-related toxicities reflecting mucosal damage, including nausea, vomiting, stomatitis, diarrhoea, abdominal pain and systemic infection. D-xylose absorption decreased and lactulose:mannitol ratio reflecting intestinal permeability increased from baseline until the second and third week after the beginning of the treatment followed by recovery. These measures correlated with infection rates, nausea, vomiting, diarrhoea and increased blood product utilization. Lisofylline was associated with increased intestinal permeability, nausea, vomiting and infection-related morbidity despite a reduction in the duration of neutropaenia. These surrogates of intestinal barrier function correlated well with clinically important outcomes despite the failure to demonstrate reduced morbidity with lisofylline and represent useful objective outcome measurements for future clinical trials of products for the amelioration of the effects of cytotoxic therapy on the intestinal mucosa.
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PMID:Intestinal mucosal dysfunction and infection during remission-induction therapy for acute myeloid leukaemia. 1708 79

To investigate the efficacy of using recombinant human interleukin 11 (rhIL-11) to reduce the need for platelet transfusions, we performed a randomized, double-blind phase II/III study with 110 acute myelogenous leukemia (AML) patients in the first complete remission. Following chemotherapy patients were subcutaneously administered either placebo (n=37) or rhIL-11 at a dose of 25 microg/kg (n=37) or 50 microg/kg (n=36). rhIL-11 administration was well tolerated. There was no difference between the rhIL-11 and placebo groups in the frequency and volume of platelet transfusions. In a perprotocol analysis set (101 patients), the platelet transfusion frequency in the 50-microg/kg group (3.0 +/- 1.76 times) was significantly lower than in the placebo group (3.9 +/-2.35 times; multiplicity-adjusted P= .049). We analyzed infection-related events retrospectively. The frequency of fever was significantly decreased in the 50-microg/kg, 25-microg/kg, and placebo groups (66.7%, 70.3%, and 89.2%, respectively; P= .018, Cochran-Armitage test). Stomatitis was less frequent in the 50-microg/kg and 25-microg/kg groups (2.8% and 0%, respectively) than in the placebo group (21.6%, P= .0012). These results show that rhIL-11 does not reduce the platelet transfusion requirement in AML patients, but the retrospective analysis confirms the previous finding that rhIL-11 reduces infection in patients undergoing chemotherapy.
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PMID:A multicenter randomized, double-blind, placebo-controlled late-phase II/III study of recombinant human interleukin 11 in acute myelogenous leukemia. 1726 3

The standard treatment for refractory oral chronic graft versus host disease (GVHD) has not been established. We present a case of AML accompanied by oral chronic GVHD in a 55-year-old man after allogeneic stem cell transplantation. The stomatitis of the patient was prolonged for a year and resistant to standard immunosuppressant therapy, including systemic administration of prednisolone and tacrolimus; however, local injection of 0.2% dexamethasone (0.5 mg per cm2) into the ulcerative area was drastically effective in improving refractory mucositis and mitigated a vicious cycle of mucosal damage and poor oral hygiene.
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PMID:[Topical steroid injection for refractory oral chronic graft-versus-host disease]. 1808 May 11

At concentrations >0.1 mM, hydroxyurea (HU) enhances the accumulation of cytosine arabinoside (ara-C) in leukemia cells in vitro. This study of children with refractory acute leukemia was designed to take advantage of this biochemical modulation. A fixed dose of HU and an escalating dose of ara-C were used. Oral HU (1200 mg/m2) was followed 2 hours later by ara-C (250-3100 mg/m2) intravenously in 15 minutes. The combination was given on days 1, 2, 3 and 8, 9, 10. Thirty-three children [26 acute lymphocytic leukemia (ALL), 7 acute nonlymphocytic leukemia] were treated; 29 received at least 1 full course. All patients developed grade 4 cytopenias. Other grade 3 to 4 toxicities included hyperbilirubinemia (2), elevated transaminases (3), transient gait disturbance (1), stomatitis (3), typhlitis (1), nausea/vomiting (9), and marrow aplasia >4 weeks (1). Three patients had intracranial bleeds while thrombocytopenic. Only liver toxicities and nausea/vomiting exhibited any dosage effect. The maximum tolerated dose of ara-C was 2400 mg/m2. There were 6 complete responses (5 ALL), 5 partial responses (3 ALL), and 19 patients with no response or progressive disease. There was no dosage effect for response with 2 complete responses occurring at the lowest ara-C level. Responses were transient (1 to 3 mo). Twenty of twenty-six patients achieved a peak serum HU level >0.5 mM by 2 hours after the HU dose. The mean level at 2 hours was 0.57 mM (range: 0.21 to 0.99 mM). This combination of HU and ara-C is tolerable and has efficacy in refractory leukemias. Responses at the lowest ara-C dose level suggests synergism.
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PMID:Sequential oral hydroxyurea and intravenous cytosine arabinoside in refractory childhood acute leukemia: a pediatric oncology group phase 1 study. 1845 68

Pediatric lymphoblastic lymphoma (LL) has utilized treatment strategies similar to childhood acute lymphoblastic leukaemia (ALL) with prolonged maintenance chemotherapy. We report the results of a pilot study to estimate the feasibility, toxicity and efficacy of a 12-month aggressive multi-agent chemotherapy regimen in children and adolescents with advanced LL. Between July 1994 and June 1997, 85 eligible children and adolescents with advanced LL (Stage III/IV) were enrolled on this pilot study. Patients achieving a complete response following induction and consolidation received six cycles of maintenance chemotherapy for a total duration of 12 months. Grade III/IV toxicities included: hematological (80%), infections (20%), stomatitis and elevated transaminases, (29%). There were a total of 19 events, 13 relapses, two secondary acute myeloid leukaemia and four toxic deaths (5%). The 5-year event-free survival (EFS) and overall survival (OS) was 78 +/- 4.5% and 85 +/- 3.9%, respectively. Relapsed patients had a 5-year OS of only 33 +/- 14%. Multivariate analysis failed to demonstrate age, gender, lactate dehydrogenase level, presence of marrow and/or central nervous system disease to have independent prognostic value. These results suggest that this experimental approach is safe and results in similar outcomes as more prolonged childhood ALL regimens.
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PMID:Shortened intensified multi-agent chemotherapy and non-cross resistant maintenance therapy for advanced lymphoblastic lymphoma in children and adolescents: report from the Children's Oncology Group. 1875 68

We evaluated the efficacy and safety of the conditioning regimen that consisted of TBI and melphalan (L-PAM), followed by hematopoietic SCT (HSCT) in 23 children with advanced hematological malignancies. The median age at HSCT was 9 (range, 2-15) years. The underlying diseases were ALL in 16 patients (5 in CR2, 3 in CR3, 6 in relapse (RP) and 2 in induction failure (IF)), AML in 4 patients (3 in RP and 1 in IF) and non-Hodgkin's lymphoma in 3 patients (1 in CR3, 1 in CR4 and 1 in RP). The stem cell sources were BM for 19 patients and cord blood for 4 patients. All patients received the conditioning regimen that consisted of TBI 12 or 13.2 Gy and L-PAM 210 mg/m(2). In all, 22 patients engrafted on the median of day 16 (range, 10-23). The regimen was well tolerated and common regimen-related toxicities (RRTs) included grade II stomatitis and grade I hepatic toxicity. The cumulative incidences of RP and TRM were 47.6 and 21.5%, respectively. At a median follow-up of 24.4 months, the probability of disease-free survival was 41.0%. The regimen may provide sufficient anti-leukemic effect without increased RRT for advanced pediatric hematological malignancies.
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PMID:TBI and melphalan followed by allogeneic hematopoietic SCT in children with advanced hematological malignancies. 2104 10


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