12 research outputs found
Safety and Efficacy of Subcutaneous Rituximab in Previously Untreated Patients with CD20+ Diffuse Large B-Cell Lymphoma or Follicular Lymphoma: Results from an Italian Phase IIIb Study
Subcutaneous (SC) rituximab may be beneficial in terms of convenience and tolerability, with potentially fewer and less severe administration-related reactions (ARRs) compared to the intravenous (IV) form. This report presents the results of a phase IIIb study conducted in Italy. The study included adult patients with CD20+ DLBCL or FL having received at least one full dose of IV RTX 375 mg/m2 during induction or maintenance. Patients on induction received ≥4 cycles of RTX SC 1400 mg plus standard chemotherapy and FL patients on maintenance received ≥6 cycles of RTX SC. Overall, 159 patients (73 DLBCL, 86 FL) were enrolled: 103 (54 DLBCL, 49 FL) completed induction and 42 patients with FL completed 12 maintenance cycles. ARRs were reported in 10 patients (6.3%), 3 (4.2%) with DLBCL and 7 (8.1%) with FL, all of mild severity, and resolved without dose delay/discontinuation. Treatment-emergent adverse events (TEAEs) and serious adverse events occurred in 41 (25.9%) and 14 patients (8.9%), respectively. Two patients with DLBCL had fatal events: Klebsiella infection (related to rituximab) and septic shock (related to chemotherapy). Neutropenia (14 patients, 8.9%) was the most common treatment-related TEAE. Two patients with DLBCL (2.8%) and 6 with FL (7.0%) discontinued rituximab due to TEAEs. 65.2% and 69.7% of patients with DLBCL and 67.9% and 73.6% of patients with FL had complete response (CR) and CR unconfirmed, respectively. The median time to events (EFS, PFS, and OS) was not estimable due to the low rate of events. At a median follow-up of 29.5 and 47.8 months in patients with DLBCL and FL, respectively, EFS, PFS, and OS were 70.8%, 70.8%, and 80.6% in patients with DLBCL and 77.9%, 77.9%, and 95.3% in patients with FL, respectively. The switch from IV to SC rituximab in patients with DLBCL and FL was associated with low risk of ARRs and satisfactory response in both groups. This trial was registered with NCT01987505
High Resistance Rate of Chronic Myeloid Leukaemia (CML) to Imatinib Myselate (IM) Might be Related to Protein Tyrosine Phosphatase Receptor Type Gamma (PTPRG) Down-Regulation
CML is the most common myeloproliferative disease observed among adults, its 1st line of treatment is IM with a response rate ranging between 55 - 90%. In Qatar the resistance rate is higher than 45%. Our collaborators in Italy recently reported on the relation between CML and PTPRG.Our team reported previously on the high rate of resistance of CML
to IM (45%). During this forum the team is further reporting on the possible underlying mechanisms behind this resistance (see Al-Dewik et al at this forum).Despite a few positive findings, no pattern could be identified to delineate a significant underlying mechanism. Our collaborators in Italy, identified that down-regulation of PTPRG increased
colony formation in the PTPRG+ve megakaryocytic MEG-01 and LAMA-84, but had no effect in the PTPRG-ve K562 and KYO-1. Its over-expression had an oncosuppressive effect in all four cell lines and is
associated with inhibition of BCR/ABL-dependent signalling. PTPRG was downregulated at the mRNA and protein levels in CML patients in both PB and BM, including CD34+ cells, and is re-expressed following molecular remission of disease.
This re-expression was associated with loss of methylation of a CpG island of PTPRG promoter in 55% patients. In K562 cells, the hypomethylating agent 5-aza-2’-deoxycytidine induced PTPRG expression and caused inhibition of colony formation that was partially reverted by antisense-mediated downregulation of PTPRG expression.
Conclusions: Although this study was done on 2 independent patient populations, it suggests that in CML populations with high resistance rate it might be worth examining the PTPRG expression level and correlate it with the pattern of resistance. Our group has secured 3 years funding from QNRF (NPRP 4-157-3-052) to investigate PTPRG signalling in CML, including the study of a possible link among the high CML resistance and the PTPRG expression levels
Synthesis and cytotoxicity of novel hexahydrothieno-cycloheptapyridazinone derivatives
Designed as a new group of tricyclic molecules containing the thienocycloheptapyridazinone ring system, a number of 2N-substituted-hexahydrothieno-cycloheptapyridazinone derivatives were synthesized and their biological activity evaluated. Among the synthesized compounds, derivatives 7d and 7h were found to possess cytotoxic activity against non-small cell lung cancer and central nervous system cancer cell lines, respectively
Down-regulation of protein tyrosine phosphatase gamma (PTPRG) in chronic myeloid leukemia (CML)
Background. Chronic Myelogenous Leukemia (CML) is the most common
myeloproliferative disease while Receptor Protein Tyosine Phosphatase
Gamma (PTPRG) has been implicated as a candidate tumor suppressor
gene being its expression reduced in various neoplasms and
somatic mutation detected in colon cancer. PTPRG regulates murine
hemopoiesis and is expressed in specific hematopoietic lineages including
CD34+ cells. Aims. Explore the possibility that PTPRG could be
involved in the pathogenesis of CML. Methods. mRNA and protein levels
were measured in cell lines, bone marrow and peripheral blood cells
by real-time PCR and flow cytometry using a newly developed antibody
specific for the extracellular domain of PTPRG. Proliferation, clonogenic
and xenografting assays were used to study the effect of PTPRG cDNA
transfection in CML cell lines. Results. We found that PTPRG expression
was undetectable in two of four CML cell lines analyzed. Its loss correlates
with higher clonogenicity and proliferation capabilities, while reexpression
inhibits both parameters, reduces tyrosine phosphorylation
and induces myeloid differentiation in stably transfected K562 cells. The
oncosuppressive and differentiation-inducing effect of PTPRG was confirmed
in vivo after xenotransplantation in a nude mice model. PTPRG
is down regulated at mRNA and protein levels in leukocytes of CML (but
not of chronic lymphocytic leukemia-CLL) patients in both peripheral
blood and bone marrow, including CD34+ cells, and is reexpressed following
molecular remission of the disease. Conclusions. Loss of PTPRG
expression is associated to the pathogenesis of CML and designate
PTPRG as a new pharmacological target. Measurement of PTPRG
expression levels might find clinical application for confirming diagnosis
and for following progression of disease and treatment
Multitarget-directed tricyclic pyridazinones as g protein-coupled receptor ligands and cholinesterase inhibitors.
By following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected G protein-coupled receptors (GPCRs) and inhibitors of acetyl and/or butyryl cholinesterase. The newly designed ligands feature pyridazinone-based tricyclic scaffolds connected through alkyl chains of variable length to proper amine moieties (e.g., substituted piperazines or piperidines) for GPCR and cholinesterase (ChE) molecular recognition. The compounds were tested at three different GPCRs, namely serotoninergic 5-HT1A, adrenergic a1A, and dopaminergic D2 receptors. Our main goal was the discovery of compounds that exhibit, in addition to ChE inhibition, antagonist activity at 5-HT1A because of its involvement in neuronal deficits typical of Alzheimer’s and other neurodegenerative diseases. Ligands with nanomolar
affinity for the tested GPCRs were discovered, but most of them behaved as dual antagonists of a1A and 5-HT1A receptors. Nevertheless, several compounds displaying this GPCR affinity profile also showed moderate to good inhibition of AChE and BChE, thus deserving further investigations to exploit the therapeutic potential of such unusual biological profiles
Multitarget-directed tricyclic pyridazinones as g protein-coupled receptor ligands and cholinesterase inhibitors
By following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected G protein-coupled receptors (GPCRs) and inhibitors of acetyl and/or butyryl cholinesterase. The newly designed ligands feature pyridazinone-based tricyclic scaffolds connected through alkyl chains of variable length to proper amine moieties (e.g., substituted piperazines or piperidines) for GPCR and cholinesterase (ChE) molecular recognition. The compounds were tested at three different GPCRs, namely serotoninergic 5-HT1A, adrenergic α1A, and dopaminergic D2 receptors. Our main goal was the discovery of compounds that exhibit, in addition to ChE inhibition, antagonist activity at 5-HT1A because of its involvement in neuronal deficits typical of Alzheimer’s and other neurodegenerative diseases. Ligands with nanomolar affinity for the tested GPCRs were discovered, but most of them behaved as dual antagonists of α1A and 5-HT1A receptors. Nevertheless, several compounds displaying this GPCR affinity profile also showed moderate to good inhibition of AChE and BChE, thus deserving further investigations to exploit the therapeutic potential of such unusual biological profiles
Protein Tyrosine Phosphatase Receptor Type \u3b3 Is a Functional Tumor Suppressor Gene Specifically Downregulated in Chronic Myeloid Leukemia
Chronic myelogenous leukemia (CML) is the most common myeloproliferative disease. Protein tyrosine phosphatase receptor type \u3b3 (PTPRG) is a tumor suppressor gene and a myeloid cell marker expressed by CD34+ cells. Downregulation of PTPRG increases colony formation in the PTPRG-positive megakaryocytic cell lines MEG-01 and LAMA-84 but has no effect in the PTPRG-negative cell lines K562 and KYO-1. Its overexpression has an oncosuppressive effect in all these cell lines and is associated with myeloid differentiation and inhibition of BCR/ABL-dependent signaling. The intracellular domain of PTPRG directly interacts with BCR/ABL and CRKL, but not with signal transducers and activators of transcription 5. PTPRG is downregulated at the mRNA and protein levels in leukocytes of CML patients in both peripheral blood and bone marrow, including CD34+ cells, and is reexpressed following molecular remission of disease. Reexpression was associated to a loss of methylation of a CpG island of PTPRG promoter occurring in 55% of the patients analyzed. In K562 cell line, the DNA hypomethylating agent 5-aza-2\u2032-deoxycytidine induced PTPRG expression and caused an inhibition of colony formation, partially reverted by downregulation of PTPRG expression. These findings establish, for the first time, PTPRG as a tumor suppressor gene involved in the pathogenesis of CML, suggesting its use as a potential diagnostic and therapeutic target