dinoprost and Leukemia--Lymphocytic--Chronic--B-Cell

Monoclonal B Lymphocytosis (MBL) is defined as asymptomatic monoclonal B-cell expansion characterised by a CLL-phenotype, but with less than 5×10(9)/l circulating cells. Reactive oxygen species (ROS)-mediated cell damage plays a critical role in the initiation of carcinogenesis as well as in malignant transformation. The goal of this study was to perform an analysis of the oxidative stress statuses of patients affected by MBL and chronic lymphocytic leukaemia (CLL). We examined peripheral blood and urine specimens from 29 patients with MBL, 55 with CLL and 31 healthy subjects. There was a significant increase in the occurrence of the mutagenic base 8-oxo-2'-deoxiguanosine (8-oxo-dG) in the lymphocytes and urine of MBL and CLL patients compared with controls. Significant differences were also observed in the levels of the lipid peroxidation product malondialdehyde (MDA) and in the oxidised/reduced glutathione (GSSG/GSH) ratio, although an increase in 8-isoprostane was not detected. Interestingly, the antioxidant catalase activity of circulating lymphocytes decreased in the patient groups. In conclusion, early oxidative stress exists in patients with MBL and CLL, causing damage to DNA and lipid structures. The higher levels of 8-oxo-dG in lymphocytes than in urine may be related to a decrease in the capacity of DNA repair systems. There were no differences in the oxidative statuses of the MBL and CLL patients, suggesting that oxidative injuries appear during a pre-leukaemic state of the disease.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; B-Lymphocytes; Biomarkers; Chromatography, High Pressure Liquid; Deoxyguanosine; Dinoprost; DNA Damage; Female; Glutathione; Glutathione Disulfide; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Reactive Oxygen Species; Time Factors

We recently reported that activated normal human B lymphocytes express Cox-2. These findings prompted us to evaluate whether human B-CLL cells express Cox-2 and synthesize prostaglandins. In contrast to naive human B cells, B-CLL cells constitutively expressed Cox-2 protein and produced PGE2, PGF2alpha, and TXA2. Elevated Cox-2 expression was seen in a subgroup of B-CLL cells that exhibit poor prognostic factors, including unmutated variable heavy chain status and increased CD38 expression. Furthermore, stimulation of B-CLL cells with CD40 ligand plus TNFalpha increased Cox-2 levels. The role of Cox-2 in promoting B-CLL survival was investigated using nonselective and selective Cox-2 inhibitors. Significant reductions in B-CLL survival occurred following Cox-2 inhibition. These new findings support that constitutive Cox-2 expression in B-CLL cells promotes their survival and possibly their expansion in vivo. It will therefore be important to evaluate drugs that inhibit Cox-2 as potential therapeutic agents in B-CLL in vivo.

Topics: B-Lymphocytes; Cell Growth Processes; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprost; Dinoprostone; Enzyme Activation; Humans; Immunoglobulin Heavy Chains; Immunohistochemistry; Indomethacin; Isoxazoles; Leukemia, Lymphocytic, Chronic, B-Cell; Nitrobenzenes; Pyrazoles; Sulfonamides; Sulfones; Thromboxane A2

The ability of prostaglandins (PG) to inhibit the growth of B cell lymphomas was investigated. Macrophage-secreted PGE2 was previously shown to promote unresponsiveness to antigen in normal B lymphocytes. This observation suggested that B lymphomas might also be regulated by prostanoids. Five non-PG-secreting Ly-1+ B lymphomas (CH12, CH31, CH33, NBL and WEHI-231) were incubated for 24-72 h with PGE2, PGE1 or PGF2 alpha. The level of lymphoma growth at the end of culture was determined using a colorimetric assay which detects only viable cells. A marked heterogeneity was observed with respect to the sensitivity of these lymphomas to PGE2 and PGE1. CH31 was very sensitive, being growth inhibited by as little as 10(-8) M PGE. In contrast, CH12, a more mature lymphoma, was highly resistant, whereas CH33, NBL and WEHI-231 were of intermediate resistance. All five lymphomas demonstrated little or no growth inhibition when cultured with PGF2 alpha. Moreover, unlike PGE2, PGF2 alpha failed to elevate intracellular cAMP levels. It was previously shown that CH31, CH33 and WEHI-231 could be growth inhibited by anti-immunoglobulin antibodies which cross-link surface immunoglobulin. Interestingly, these three lymphomas were rendered more sensitive to this treatment if PGE2 was present. For example, 10(-8) M PGE2 alone had little effect on CH33, but significantly augmented growth inhibition induced by suboptimal quantities of anti-immunoglobulin antibody. Cholera toxin, another agent which was found to rapidly elevate intracellular cAMP levels, also synergized with suboptimal doses of anti-immunoglobulin to induce growth inhibition. Overall these data suggest that, in vivo, macrophage-secreted prostanoids may slow the growth of some lymphomas and that anti-immunoglobulin or anti-idiotype treatment may be more effective in the presence of agents which elevate cAMP such as E-series PG.

Topics: Animals; B-Lymphocytes; Cell Division; Cholera Toxin; Cyclic AMP; Dinoprost; Drug Administration Schedule; Drug Synergism; Growth Inhibitors; In Vitro Techniques; Leukemia, Lymphocytic, Chronic, B-Cell; Mice; Prostaglandins E; Receptors, Antigen, B-Cell; Tumor Cells, Cultured

A study was made of the effect of exogenous prostaglandins E1, E2 and E2 alpha on the proliferative response of lymphocytes in blast transformation with PHA according to the changes in permeability for 3H-thymidine, 3H-thymidine incorporation into DNA, 3H-uridine into RNA and 3H-leucine into protein in 7 patients with stable and in 17 patients with progressive B-chronic lymphoid leukemia (B-CLL). The progression of B-CLL was marked by the lack of the regulating effect of PG on lymphocytes. In stable lymphoid leukemia, an inhibitory action of PG on lymphocyte proliferation could be seen. The characteristics of the lymphocyte responses in patients with B-CLL were employed for individual prediction of the disease course.

Topics: Adjuvants, Immunologic; Alprostadil; B-Lymphocytes; Dinoprost; Dinoprostone; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Activation; Prognosis; Prostaglandins; Tritium; Tumor Cells, Cultured