Subject(s)
Biomarkers, Tumor/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/enzymology , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Mutation/genetics , Protein Kinases/genetics , DNA, Neoplasm/genetics , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Polymerase Chain Reaction , Sequence Analysis, DNAABSTRACT
Kaposi's sarcoma (KS)-associated herpes virus (KSHV) is the causative agent of primary effusion lymphoma and of KS. Primary effusion lymphoma (PEL) is an aggressive proliferation of B cells. Conventional chemotherapy has limited benefits in PEL patients, and the prognosis is very poor. We previously reported that treatment of human T-cell leukemia virus type 1 (HTLV-1)-associated adult T-cell leukemia/lymphoma cells either with arsenic trioxide (As) combined to interferon-alpha (IFN-alpha) or with the bortezomib (PS-341) proteasome inhibitor induces cell cycle arrest and apoptosis, partly due to the reversal of the constitutive nuclear factor-kappaB (NF-kappaB) activation. PEL cells also display an activated NF-kappaB pathway that is necessary for their survival. This prompted us to investigate the effects of PS-341, or of the As/IFN-alpha combination on PEL cells. A dramatic inhibition of cell proliferation and induction of apoptosis was observed in PS-341 and in As/IFN-alpha treated cells. This was associated with the dissipation of the mitochondrial membrane potential, cytosolic release of cytochrome c, caspase activation and was reversed by the z-VAD caspase inhibitor. PS-341 and As/IFN-alpha treatment abrogated NF-kappaB translocation to the nucleus and decreased the levels of the anti-apoptotic protein Bcl-X(L). Altogether, these results provide a rational basis for a future therapeutic use of PS-341 or combined As and IFN-alpha in PEL patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis/drug effects , Boronic Acids/pharmacology , Caspases/metabolism , Herpesvirus 8, Human/physiology , Lymphoma/pathology , Lymphoma/virology , Pyrazines/pharmacology , Arsenic Trioxide , Arsenicals/administration & dosage , Bortezomib , Cell Proliferation/drug effects , Humans , Interferon-alpha/administration & dosage , Lymphoma/enzymology , Membrane Potential, Mitochondrial/drug effects , NF-kappa B/metabolism , Oxides/administration & dosage , Protease Inhibitors/pharmacology , bcl-X Protein/metabolismABSTRACT
Patients with severe haemophilia can be treated for bleeding either prophylactically or on demand. Each treatment modality has advantages and disadvantages from both a medical and economic point of view. This study aims to find which modality requires more units of clotting factors per body weight per year and to compare the number of bleeds between the two. The study sample consisted of 133 patients with severe haemophilia A and B treated in the Katharine Dormandy Haemophilia Centre at the Royal Free Hampstead NHS Trust in London. The average number of clotting factors used per body weight per year was 2181.7 units for prophylaxis vs. 711 units for on demand treatment (P = 0.000). Although more units used means more money spent, and although prophylaxis has additional complications, namely venipunctures and increased risk of viral contamination, other criteria must be considered including the total number of bleeds and health-related quality of life. The total number of bleeds per year was significantly (P = 0.021) less for prophylactically (7.4) vs. on-demand treated patients (11.4). This suggests that prophylaxis reduces the risk of arthropathies, the number of future hospital visits and orthopaedic surgeries, and is thus the optimal modality of treatment for patients with severe haemophilia.
