Abstract:Adenosine 3',5'-monophosphate, at a concentration of 40 micrograms per milliliter, inhibits the growth of HeLa and strain L cells in culture. The inhibition becomes progressively greater during the incubation of the cells. Adenosine 5'-monophosphate and adenosine, metabolites of adenosine 3',5'-monophosphate, do not affect the growth of either cell culture. This suggests that 3',5'-monophosphate enters the cell without alteration. Dibutyryl-adenosine 3',5'-monophosphate, reported to have a greater activity tha… Show more
“…Thus, in skin c-AMP levels fluctuate with a pronounced diurnal rhythm, reaching a maximum during the resting phase of growth (Marks and Grimm, 1972). In vitro, c-AMP, dibutyryl cyclic AMP and ISOP also inhibit DNA synthesis in PHAand concanavalin A stimulated lymphocytes (Abell, Kamp and Johnson, 1970;Johnson and Abell, 1970;Krug et al, 1972) and the growth of HeLa and L cells (Ryan and Heidrick, 1968). Otten, Johnson and Pastan (1971) studied fibroblasts in logarithmic growth phase and growth of virus transformed 3T3 cells in vitro; they found that intracellular levels of c-AMP were inversely proportional to DNA synthesis.…”
These findings, correlated with measurements of cyclic AMP in the lungs of normal and stressed rats, suggest that changes in the resistance of the host to tumour growth involve changes in cyclic nucleotide metabolism in the target tissues (tumour bed); possible mechanisms of action of cyclic nucleotides in this respect are discussed.
“…Thus, in skin c-AMP levels fluctuate with a pronounced diurnal rhythm, reaching a maximum during the resting phase of growth (Marks and Grimm, 1972). In vitro, c-AMP, dibutyryl cyclic AMP and ISOP also inhibit DNA synthesis in PHAand concanavalin A stimulated lymphocytes (Abell, Kamp and Johnson, 1970;Johnson and Abell, 1970;Krug et al, 1972) and the growth of HeLa and L cells (Ryan and Heidrick, 1968). Otten, Johnson and Pastan (1971) studied fibroblasts in logarithmic growth phase and growth of virus transformed 3T3 cells in vitro; they found that intracellular levels of c-AMP were inversely proportional to DNA synthesis.…”
These findings, correlated with measurements of cyclic AMP in the lungs of normal and stressed rats, suggest that changes in the resistance of the host to tumour growth involve changes in cyclic nucleotide metabolism in the target tissues (tumour bed); possible mechanisms of action of cyclic nucleotides in this respect are discussed.
“…In vitro, exogenous cGMP stimulates the proliferation of fibroblasts and lymphoid cells Whitfield et al, 1971;Diamantstein & Ulmer, 1975;Watson, 1975) whereas cAMP, or agents which increase its intracellular concentration, inhibit cell growth (Ryan & Heidrick, 1968;Yang & Vas, 1971;Pardee, 1974) and induce in malignant cells a normalappearing morphological or biochemical differentiation (Hsie & Puck, 1971;Johnson et al, 1971;Prasad et al, 1975).…”
Summary.-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 in all mononuclear-leucocyte preparations with the methods used.
“…2B) Bt2cAMP (18-21; B. E. Ledford and J. Papaconstantinou, manuscript in preparation). In addition, intracellular cAMP levels have been shown to increase with cell density (22)(23)(24). In view of the above, cultures were treated with Btt2cAMP to determine whether the generation time of the FLC is altered and whether this, in turn, is reflected in the time of appearance of hemoglobin.…”
The induction of hemoglobin synthesis by dimethylsulfoxide in cells infected with Friend leukemia virus has been shown to depend on the number of cell divisions after the addition of the inducing agent. In asynchronous cultures the cells have a generation time of 24 hr, and hemoglobin synthesis occurs after 48 hr in the presence of dimethylsulfoxide. Generation times were extended by lowering the serum content of the medium. In 7.5% and 2.5% fetal calf serum, the generation time was increased to 36 hr and 48 hr, respectively, and hemoglobin synthesis began at 72 hr and 96 hr, respectively. In the presence of N6,02'-dibutyryladenosine 3':5'-cyclic monophosphate the generation time was extended to 38 hr, and hemoglobin synthesis began after 72 hr in dimethylsulfoxide.The number of cell doublings, under conditions where the generation time was 24 hr, was regulated by the size of the initial cell concentration. When a low inoculum (1.5 X 105 cells per cm') was used, the culture was still in log phase after two doublings and hemoglobin appeared in log phase; a moderate initial inoculum (4.2 X 105 cells per cm3) took the culture into stationary phase after two doublings, and hemoglobin synthesis was induced in stationary-phase cells. Heavy inocula (3.7 X 106 cells per cm') maintained the cells in stationary phase, and under these conditions no induction of hemoglobin synthesis occured. We conclude from these studies that the initiation of hemoglobin synthesis required two rounds of mitosis after treatment with dimethylsulfoxide.In studies with synchronized cultures of cells infected with Friend leukemia virus, two mitoses were required for the initiation of hemoglobin synthesis. We conclude that two rounds of DNA synthesis and/or mitosis are also required for the dimethylsulfoxide-mediated induction of erythroid differentiation and hemoglobin synthesis in these cells.
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