ABSTRACT
L-asparaginase is a frequently used drug in the treatment of canine malignant lymphoma. Since production and availability of native E. coli-derived L-asparaginase are limited, PEG-L-asparaginase (PEG-ASP) is an alternative. However, recommended doses and dosing intervals are mainly empirically determined. A multi-phase clinical dose-finding study with seven healthy Beagle dogs was conducted to find the minimum effective dose and, potentially, a dosing interval for PEG-ASP in dogs. Plasma concentrations of amino acids and PEG-ASP activity were measured at various time points after administration of different doses of PEG-ASP. Anti-PEG and anti-asparaginase antibody titres were measured. Administration of 10 IU/kg PEG-ASP resulted in asparagine depletion in all dogs, albeit for various durations: for 9 days in all dogs, 15 days in five dogs, 21 days in three dogs and 29 days in one dog. Asparagine suppression occurred at PEG-ASP plasma concentrations < 25 IU/L. Subsequent administrations of a second and third dose of 20 IU/kg and 40 IU/kg PEG-ASP resulted in asparagine suppression at < 9 days in five dogs, accompanied by the development of antibodies against PEG and L-asparaginase. Two dogs with prolonged asparagine suppression after the second and third administration did not develop antibodies. Marked individual variation in the mechanism and duration of response to PEG-ASP was noted. Antibody formation against PEG-ASP was frequently observed and sometimes occurred after one injection. This study suggests that PEG-ASP doses as high as the currently used dose of 40 IU/kg might not be needed in treatment of canine malignant lymphoma.
Subject(s)
Antineoplastic Agents , Dog Diseases , Lymphoma , Animals , Antineoplastic Agents/therapeutic use , Asparagine/therapeutic use , Dog Diseases/drug therapy , Dogs , Escherichia coli , Lymphoma/drug therapy , Lymphoma/veterinary , Polyethylene Glycols/therapeutic useABSTRACT
The MYB oncogene is a leucine zipper transcription factor essential for normal and malignant hematopoiesis. In T-cell acute lymphoblastic leukemia (T-ALL), elevated MYB levels can arise directly through T-cell receptor-mediated MYB translocations, genomic MYB duplications or enhanced TAL1 complex binding at the MYB locus or indirectly through the TAL1/miR-223/FBXW7 regulatory axis. In this study, we used an unbiased MYB 3'untranslated region-microRNA (miRNA) library screen and identified 33 putative MYB-targeting miRNAs. Subsequently, transcriptome data from two independent T-ALL cohorts and different subsets of normal T-cells were used to select miRNAs with relevance in the context of normal and malignant T-cell transformation. Hereby, miR-193b-3p was identified as a novel bona fide tumor-suppressor miRNA that targets MYB during malignant T-cell transformation thereby offering an entry point for efficient MYB targeting-oriented therapies for human T-ALL.
Subject(s)
Gene Expression Regulation, Leukemic , MicroRNAs/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Proto-Oncogene Proteins c-myb/genetics , T-Lymphocytes/metabolism , 3' Untranslated Regions , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , F-Box Proteins/genetics , F-Box Proteins/metabolism , F-Box-WD Repeat-Containing Protein 7 , Gene Expression Profiling , Genomic Library , Humans , Mice , MicroRNAs/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Primary Cell Culture , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-myb/metabolism , Signal Transduction , T-Cell Acute Lymphocytic Leukemia Protein 1 , T-Lymphocytes/pathology , Transcriptome , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolismABSTRACT
The calcium-sensing receptor (CaSR) belongs to the evolutionarily conserved family of plasma membrane G protein-coupled receptors (GPCRs). Early studies identified an essential role for the CaSR in systemic calcium homeostasis through its ability to sense small changes in circulating calcium concentration and to couple this information to intracellular signaling pathways that influence parathyroid hormone secretion. However, the presence of CaSR protein in tissues is not directly involved in regulating mineral ion homeostasis points to a role for the CaSR in other cellular functions including the control of cellular proliferation, differentiation and apoptosis. This position at the crossroads of cellular fate designates the CaSR as an interesting study subject is likely to be involved in a variety of previously unconsidered human pathologies, including cancer, atherosclerosis and Alzheimer's disease. Here, we will review the recent discoveries regarding the relevance of CaSR signaling in development and disease. Furthermore, we will discuss the rational for developing and using CaSR-based therapeutics.
