cyclic-gmp and Leukemia--Lymphoid

Topics: Cells, Cultured; Cyclic AMP; Cyclic GMP; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lymphocytes; Prostaglandins E

Topics: Adolescent; Child; Child, Preschool; Cyclic AMP; Cyclic GMP; Humans; Leukemia, Lymphoid; Leukocytes; Neoplasm Recurrence, Local

Topics: Adult; Aged; Cells, Cultured; Cyclic AMP; Cyclic GMP; Folic Acid; Humans; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lymphocytes; Middle Aged; Prostaglandins E; Sialic Acids; Vitamin B 12

Because recent observations indicate that metabolism of cyclic nucleotides may be altered in neoplastic cells, the intracellular levels of cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP) were measured in mononuclear leukaemic and normal human leucocytes. The activities of adenylate cyclase, guanylate cyclase and cyclic nucleotide phosphodiesterases were also determined. Under basal conditions, cAMP levels were always higher in the normal leucocytes, whilst cGMP levels were of the same order of magnitude in both normal and leukaemic cells, causing the cAMP/cGMP ratios to be significantly lower in leukaemic leucocytes. Leukaemic cells significantly increased cyclic nucleotide levels in response to theophylline, but did not respond to serotonin, carbamylcholine or D,L-isoproterenol. Preincubation of these leucocytes with theophylline produced a detectable cAMP response to D,L-isoproterenol but no cGMP response to serotonin or carbamylcholine was found. Adenylate cyclase and guanylate cyclase were significantly lower in leukaemic than in normal cells, which could largely explain the abnormal cyclic nucleotide pattern found in human leukaemic leucocytes. In our experiments, cAMP phosphodiesterase activity was comparable in normal and leukaemic cells, whereas cGMP phosphodiesterase activity was undetectable inall mononuclear-leucocyte preparations with the methods used.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adenylyl Cyclases; Carbachol; Cyclic AMP; Cyclic GMP; Guanylate Cyclase; Humans; Isoproterenol; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Leukocytes; Serotonin; Theophylline

Experiments were performed to characterize the protein kinase activity in blood lymphocytes from patients with chronic lymphocytic leukemia (CLL). Using histone as a substrate, the average specific activity was 397 pmole/min/mg protein. The Km for ATP was 8 muM and for histone 0.3 mg/ml. The addition of optimal concentrations of cyclic adenosine monophosphate (cAMP) (1 muM) or cyclic guanosine monophosphate (cGMP) (10muM) resulted in a 2.2-fold stimulation in activity but had no effect on the Km for ATP or histone. Most of the properties of the CCL protein kinase were similar to those of the normal lymphocyte enzyme. These include the pH response, substrate affinity, as well as rates of phosphorylation and dephosphorylation. The phosphorylation pattern of endogenous proteins was determined using intact lymphocytes incubated with 32P and cell-free homogenates with AT32P. These results indicate that: (1) the cyclicnucleotide-protein kinase interactions are unimpaired in CLL lymphocytes; and (2) a sharply defined cyclic nucleotide concentration response occurs for CLL (as well as normal) lymphocytes, which may explain the reports of variable inhibitory (and stimulatory) effects on mitogenesis by these agents.

Topics: Cyclic AMP; Cyclic GMP; Histones; Humans; Hydrogen-Ion Concentration; Leukemia, Lymphoid; Lymphocytes; Phosphorylation; Protein Kinases

Cyclic adenosine 3':5'-monophosphate-dependent protein kinase (kinase A) and cyclic guanosine 3':5'-monophosphate-dependent protein kinase (kinase G) were assayed in lymphocytes of normal subjects, adults with chronic lymphocytic leukemia (CLL), and children with acute lymphocytic leukemia (ALL). There was a good correlation between the activity of the two kinases and the level of the corresponding cyclic nucleotides. This was true for cultured phytohemagglutinin-stimulated normal lymphocytes and CLL lymphocytes as well. Kinase A activity was low and kinase G activity was high in leukemic cells in the absence of the respective cyclic nucleotides [5 and 8 units (pmol 32P incorporated into histone per min per mg protein) for kinase A and 98 and 51 units for kinase G in ALL and CLL lymphocytes, respectively]. Upon addition of cyclic adenosine 3':5'-monophosphate and cyclic guanosine 3':5'-monophosphate in vitro, values for kinase A activity returned to normal (approximately 30 units), whereas those for kinase G increased further (212 units for ALL and 85 units for CLL lymphocytes; 22 units was the kinase activity for normal lymphocytes). These findings suggest that cyclic nucleotides achieve thetr specificity in the regulation of the cell, in part, through the activation of the dependent protein kinases and that both kinase A and kinase G may be functionally intact in leukemic cells.

Topics: Adult; B-Lymphocytes; Child; Cyclic AMP; Cyclic GMP; Humans; Leukemia; Leukemia, Lymphoid; Lymphocytes; Phytohemagglutinins; Protein Kinases; T-Lymphocytes; Time Factors

The level of cyclic nucleotides in three populations of cultured human lymphocytes were studied. An early conspicuous elevation of c-GMP level and a reciprocal relationship between c-AMP and c-GMP fluctuations were demonstrated in T cells from normal donors. Null cells from patients with ALL showed a constantly low level of c-AMP, while c-GMP fluctuated in apparent relationship with cell doubling time. Persistently low levels of c-AMP and persistently high level of c-GMP were found in B cells from patients with CLL. Possible significance of these findings is discussed.

Topics: B-Lymphocytes; Cells, Cultured; Cyclic AMP; Cyclic GMP; Humans; Leukemia, Lymphoid; Lymphocytes; T-Lymphocytes

Prostaglandins E (PGE) and F2 alpha (PGF2 alpha) were measured in lymphocytes of normal subjects, children with acute lymphocytic leukemia (ALL), and adults with chronic lymphocytic leukemia (CLL). In ALL lymphocytes PGE increased from a normal value of 25 pgrams to 270 pgrams/10(6) cells, and PGF 2 alpha increased from a normal value of 31 pgrams to 482 pgrams/10(6) cells. In CLL lymphocytes, levels of PGE and PGF2 alpha were normal or low. When normal lymphocytes were stimulated with phytohemagglutinin (PHA), the level of PGE and PGF2 alpha fluctuated, followed by corresponding changes in the level of cyclic nucleotides. In cultured ALL lymphocytes, the level of PGE remained high, while cyclic 3':5'-adenosine monophosphate (c-AMP) level was constantly low, and the initial level of PGF2 alpha fluctuated in relation to similar oscillations of cyclic 3':5'-guanosine monophosphate (c-GMP). These values were lower, although not significantly, when ALL lymphocytes were stimulated with PHA. When CLL lymphocytes were stimulated with PHA, the level of PGE remained low (20 pgrams), as did that of c-AMP. The level of PGF2 alpha, after a brief initial increase (130 pgrams), returned to and remained at a lower level (60 pgrams) while the level of c-GMP was persistently high. These results suggest: (1) prostaglandins may indirectly influence the cell cycle, possibly through modulation of cyclase activity and levels of cyclic nucleotides; and (2) some derangement of this regulatory mechanism may be present in leukemic lymphocytes.

Topics: Adult; Child; Cyclic AMP; Cyclic GMP; Humans; Leukemia, Lymphoid; Lymphocytes; Phytohemagglutinins; Prostaglandins E; Prostaglandins F

Topics: Cyclic AMP; Cyclic GMP; Humans; Leukemia, Lymphoid; Neoplasms; Nucleotides, Cyclic; Polycythemia Vera; Remission, Spontaneous

Cyclic nucleotide phosphodiesterase activities were examined in lymphocytes from 12 transformed human B cell lines, two T cell lines, six patients with lymphocytic leukemia, and 10 normal donors. A consistent difference bwtween cells from the normal and leukemic state was observed. The cyclic AMP phosphodiesterase activity from normal lymphocytes is inhibited greater than 80% by muM cyclic GMP while this concentration of nucleotide has little or no effect on the enzyme from transformed lymphocytic cell lines or from lymphocytic cells of leukemia patients. The reported lack of cyclic GMP phosphodiesterase in human lymphocytes from several sources is confirmed. The apparent absence of a cyclic GMP degradation mechanism and of cyclic GMP control of cyclic AMP hydrolysis may be related to defective lymphocyte growth control.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Cyclic AMP; Cyclic GMP; Humans; Leukemia, Lymphoid; Liver; Lymphocytes; Rats

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Cyclic AMP; Cyclic GMP; Humans; Leukemia, Lymphoid; Lymphocytes; Nucleotides, Cyclic

Recent revival of interest in the use of vincristine (VCR) for the treatment of idiopathic thrombocytopenic purpura prompted us to evaluate the platelet function of our patients on VCR. Eighteen patients with acute lymphoblastic leukaemia (ALL) in remission, and nine children with solid tumours were studied on 80 occasions at different time intervals after their last VCR dose. A mildly elevated threshold for epinephrine-induced second phase aggregation and a delay in the onset of collagen-induced aggregation was found in patients with ALL not on VCR. Vincristine induced unobtainable second phase aggregation to epinephrine in 67%, 38%, 30% and to ADP in 53%, 13%, 33% of the patients 1 week, 2-3 weeks and 4 weeks respectively after administration. The thrombocytopathy was relative, not absolute, since collagen induced aggregation at all times. Platelet counts, uptake and release of serotonin, bleeding times, clot retractions and release of platelet factor 3 were normal. Platelet adhesion was abnormal in five of 12 patients tested. In vitro platelets are a hundred-fold less sensitive to VCR than in vivo. Cyclic adenosine monophosphate, cyclic guanosine monophosphate and dimethylsulfoxide do not protect platelets from VCR. The exact mechanism by which VCR abolishes second phase aggregation in patients is uncertain. Because of VCR's narrow therapeutic index between thrombocytopenia and thrombocythaemia, the use of VCR should be reserved for life-threatening haematologic disorders when treating non-malignant conditions.

Topics: Adenosine Diphosphate; Blood Platelets; Child; Cyclic AMP; Cyclic GMP; Dimethyl Sulfoxide; Epinephrine; Humans; Leukemia, Lymphoid; Platelet Adhesiveness; Platelet Aggregation; Serotonin; Vincristine

Topics: Animals; Bursa of Fabricius; Chickens; Child; Cyclic GMP; DNA Nucleotidyltransferases; Fibroblasts; Guanosine Monophosphate; Humans; Infant; Leukemia, Experimental; Leukemia, Lymphoid; Lymphocytes; Lymphoid Tissue; Mice; Moloney murine leukemia virus; Oligonucleotides; Polynucleotides; Thymus Gland