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. 1980 Mar;41(3):360–371. doi: 10.1038/bjc.1980.59

Patterns of cyclic nucleotides in normal and leukaemic human leucocytes.

M Peracchi, A T Maiolo, L Lombardi, F B Catena, E E Polli
PMCID: PMC2010252  PMID: 6104501

Abstract

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.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Atkinson J. P., Sullivan T. J., Kelly J. P., Parker C. W. Stimulation by alcohols of cyclic AMP metabolism in human leukocytes. Possible role of cyclic AMP in the anti-inflammatory effects of ethanol. J Clin Invest. 1977 Aug;60(2):284–294. doi: 10.1172/JCI108776. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baenziger N. L., Majerus P. W. Isolation of human platelets and platelet surface membranes. Methods Enzymol. 1974;31:149–155. doi: 10.1016/0076-6879(74)31015-4. [DOI] [PubMed] [Google Scholar]
  3. Ben-Zvi A., Russell A., Shneyour A., Trainin N. Cyclic-AMP in human lymphocytes: levels in acute leukemia and infectious mononucleosis. Eur J Cancer. 1979 Apr;15(4):615–617. doi: 10.1016/0014-2964(79)90100-2. [DOI] [PubMed] [Google Scholar]
  4. Bennett J. M., Catovsky D., Daniel M. T., Flandrin G., Galton D. A., Gralnick H. R., Sultan C. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol. 1976 Aug;33(4):451–458. doi: 10.1111/j.1365-2141.1976.tb03563.x. [DOI] [PubMed] [Google Scholar]
  5. Bourne H. R., Lehrer R. I., Lichtenstein L. M., Weissmann G., Zurier R. Effects of cholera enterotoxin on adenosine 3',5'-monophosphate and neutrophil function. Comparison with other compounds which stimulate leukocyte adenyl cyclase. J Clin Invest. 1973 Mar;52(3):698–708. doi: 10.1172/JCI107231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Boyd H., McAfee D. A., Laumen G., Rubin J. J. A study of cyclic nucleotide metabolism and the histology of rat liver during 3'-methyl-4-dimethylamino-azobenzene carcinogenesis. III. Cyclic GMP metabolism. Tissue Cell. 1978;10(3):495–504. doi: 10.1016/s0040-8166(16)30343-3. [DOI] [PubMed] [Google Scholar]
  7. Böyum A. Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl. 1968;97:77–89. [PubMed] [Google Scholar]
  8. Chisholm R. L., Tubergen D. G. The significance of varying SRBC/lymphocyte ratio in T cell rosette formation. J Immunol. 1976 May;116(5):1397–1399. [PubMed] [Google Scholar]
  9. Criss W. E., Murad F., Kimura H. Properties of guanylate cyclase from rat kidney cortex and transplantable kidney tumors. J Cyclic Nucleotide Res. 1976;2(1):11–19. [PubMed] [Google Scholar]
  10. DeRubertis F. R., Chayoth R., Field J. B. The content and metabolism of cyclic adenosine 3', 5'-monophosphate and cyclic guanosine 3', 5'-monophosphate in adenocarcinoma of the human colon. J Clin Invest. 1976 Mar;57(3):641–649. doi: 10.1172/JCI108320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. DeRubertis F. R., Craven P. Increased guanylate cyclase activity and guanosine 3',5'-monophosphate content in ethionine-induced hepatomas. Cancer Res. 1977 Jan;37(1):15–21. [PubMed] [Google Scholar]
  12. Deviller P., Cille Y., Betuel H. Guanyl cyclase activity of human blood lymphocytes. Enzyme. 1975;19(5-6):300–313. doi: 10.1159/000459005. [DOI] [PubMed] [Google Scholar]
  13. Diamantstein T., Ulmer A. The antagonistic action of cyclic GMP and cyclic AMP on proliferation of B and T lymphocytes. Immunology. 1975 Jan;28(1):113–119. [PMC free article] [PubMed] [Google Scholar]
  14. Friedman D. L. Role of cyclic nucleotides in cell growth and differentiation. Physiol Rev. 1976 Oct;56(4):652–708. doi: 10.1152/physrev.1976.56.4.652. [DOI] [PubMed] [Google Scholar]
  15. Goldberg N. D., Haddox M. K. Cyclic GMP metabolism and involvement in biological regulation. Annu Rev Biochem. 1977;46:823–896. doi: 10.1146/annurev.bi.46.070177.004135. [DOI] [PubMed] [Google Scholar]
  16. Goldberg N. D., Haddox M. K., Nicol S. E., Glass D. B., Sanford C. H., Kuehl F. A., Jr, Estensen R. Biologic regulation through opposing influences of cyclic GMP and cyclic AMP: the Yin Yang hypothesis. Adv Cyclic Nucleotide Res. 1975;5:307–330. [PubMed] [Google Scholar]
  17. Greaves M. F., Brown G. Purification of human T and B lymphocytes. J Immunol. 1974 Jan;112(1):420–423. [PubMed] [Google Scholar]
  18. Hickie R. A., Thompson W. J., Strada S. J., Couture-Murillo B., Morris H. P., Robison G. A. Comparison of cyclic adenosine 3':5'-monophosphate and cyclic guanosine 3':5'-monophosphate levels, cyclases, and phosphodiesterases in Morris hepatomas and liver. Cancer Res. 1977 Oct;37(10):3599–3606. [PubMed] [Google Scholar]
  19. Hsie A. W., Puck T. T. Morphological transformation of Chinese hamster cells by dibutyryl adenosine cyclic 3':5'-monophosphate and testosterone. Proc Natl Acad Sci U S A. 1971 Feb;68(2):358–361. doi: 10.1073/pnas.68.2.358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Illiano G., Tell G. P., Siegel M. E., Cuatrecasas P. Guanosine 3':5'-cyclic monophosphate and the action of insulin and acetylcholine. Proc Natl Acad Sci U S A. 1973 Aug;70(8):2443–2447. doi: 10.1073/pnas.70.8.2443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Johnson G. S., Friedman R. M., Pastan I. Restoration of several morphological characteristics of normal fibroblasts in sarcoma cells treated with adenosine-3':5'-cyclic monphosphate and its derivatives. Proc Natl Acad Sci U S A. 1971 Feb;68(2):425–429. doi: 10.1073/pnas.68.2.425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kumakura K., Frattola L., Spano P. F., Trabucchi M. Guanylate cyclase in human brain tumors: regulation of cellular growth. Pharmacol Res Commun. 1977 Jun;9(6):579–586. doi: 10.1016/s0031-6989(77)80086-6. [DOI] [PubMed] [Google Scholar]
  23. Küng W., Bechtel E., Geyer E., Salokangas A., Preisz J., Huber P., Torhorst J., Jungmann R. A., Talmadge K., Eppenberger U. Altered levels of cyclic nucleotides, cyclic AMP phosphodiesterase and adenylyl cyclase activities in normal, dysplastic and neoplastic human mammary tissue. FEBS Lett. 1977 Oct 1;82(1):102–106. doi: 10.1016/0014-5793(77)80895-8. [DOI] [PubMed] [Google Scholar]
  24. McNeill J. H., Nassar M., Brody T. M. The effect of theophylline on amine-induced cardiac phosphorylase activation and cardiac contractility. J Pharmacol Exp Ther. 1969 Feb;165(2):234–241. [PubMed] [Google Scholar]
  25. Monahan T. M., Marchand N. W., Fritz R. R., Abell C. W. Cyclic adenosine 3':5'-monophosphate levels and activities of related enzymes in normal and leukemic lymphocytes. Cancer Res. 1975 Sep;35(9):2540–2547. [PubMed] [Google Scholar]
  26. Pardee A. B. A restriction point for control of normal animal cell proliferation. Proc Natl Acad Sci U S A. 1974 Apr;71(4):1286–1290. doi: 10.1073/pnas.71.4.1286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Parker C. W., Smith J. W. Alterations in cyclic adenosine monophosphate metabolism in human bronchial asthma. I. Leukocyte responsiveness to -adrenergic agents. J Clin Invest. 1973 Jan;52(1):48–59. doi: 10.1172/JCI107173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Parker C. W., Sullivan T. J., Wedner H. J. Cyclic AMP and the immune response;. Adv Cyclic Nucleotide Res. 1974;4(0):1–79. [PubMed] [Google Scholar]
  29. Pastan I. H., Johnson G. S., Anderson W. B. Role of cyclic nucleotides in growth control. Annu Rev Biochem. 1975;44:491–522. doi: 10.1146/annurev.bi.44.070175.002423. [DOI] [PubMed] [Google Scholar]
  30. Polgar P., Vera J. C., Kelley P. R., Rutenburg A. M. Adenylate cyclase activity in normal and leukemic human leukocytes as determined by a radioimmunoassay for cyclic AMP. Biochim Biophys Acta. 1973 Feb 28;297(2):378–383. doi: 10.1016/0304-4165(73)90085-8. [DOI] [PubMed] [Google Scholar]
  31. Polgar P., Vera J. C., Rutenburg A. M. An altered response to cyclic AMP stimulating hormones in intact human leukemic lymphocytes. Proc Soc Exp Biol Med. 1977 Apr;154(4):493–495. doi: 10.3181/00379727-154-39701. [DOI] [PubMed] [Google Scholar]
  32. Preud'homme J. L., Labaume S. Immunofluorescent staining of human lymphocytes for the detection of surface immunoglobulins. Ann N Y Acad Sci. 1975 Jun 30;254:254–261. doi: 10.1111/j.1749-6632.1975.tb29175.x. [DOI] [PubMed] [Google Scholar]
  33. Rudland P. S., Seeley M., Seifert W. Cyclic GMP and cyclic AMP levels in normal and transformed fibroblasts. Nature. 1974 Oct 4;251(5474):417–419. doi: 10.1038/251417a0. [DOI] [PubMed] [Google Scholar]
  34. Ryan W. L., Heidrick M. L. Inhibition of cell growth in vitro by adenosine 3',5'-monophosphate. Science. 1968 Dec 27;162(3861):1484–1485. doi: 10.1126/science.162.3861.1484. [DOI] [PubMed] [Google Scholar]
  35. Salomon Y., Londos C., Rodbell M. A highly sensitive adenylate cyclase assay. Anal Biochem. 1974 Apr;58(2):541–548. doi: 10.1016/0003-2697(74)90222-x. [DOI] [PubMed] [Google Scholar]
  36. Sandler J. A., Clyman R. I., Manganiello V. C., Vaughan M. The effect of serotonin (5-hydroxytryptamine) and derivatives on guanosine 3',5'-monophosphate in human monocytes. J Clin Invest. 1975 Feb;55(2):431–435. doi: 10.1172/JCI107948. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Scher N. S., Quagliata F., Malathi V. G., Faig D., Melton R. A., Silber R. Cyclic adenosine 3':5'-monophosphate phosphodiesterase activity in normal and chronic lymphocytic leukemia lymphocytes. Cancer Res. 1976 Nov;36(11 Pt 1):3958–3962. [PubMed] [Google Scholar]
  38. Schultz G., Hardman J. G., Schultz K., Baird C. E., Sutherland E. W. The importance of calcium ions for the regulation of guanosine 3':5'-cyclic monophosphage levels. Proc Natl Acad Sci U S A. 1973 Dec;70(12):3889–3893. doi: 10.1073/pnas.70.12.3889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Seifert W. E., Rudland P. S. Possible involvement of cyclic GMP in growth control of cultured mouse cells. Nature. 1974 Mar 8;248(5444):138–140. doi: 10.1038/248138a0. [DOI] [PubMed] [Google Scholar]
  40. Sheppard J. R., Gormus R., Moldow C. F. Catecholamine hormone receptors are reduced on chronic lymphocytic leukaemic lymphocytes. Nature. 1977 Oct 20;269(5630):693–695. doi: 10.1038/269693a0. [DOI] [PubMed] [Google Scholar]
  41. Takemoto D. J., Lee W. N., Kaplan S. A., Appleman M. M. Cyclic AMP phosphodiesterase in human lymphocytes and lymphoblasts. J Cyclic Nucleotide Res. 1978 Apr;4(2):123–132. [PubMed] [Google Scholar]
  42. Thompson W. J., Appleman M. M. Multiple cyclic nucleotide phosphodiesterase activities from rat brain. Biochemistry. 1971 Jan 19;10(2):311–316. [PubMed] [Google Scholar]
  43. Thompson W. J., Ross C. P., Pledger W. J., Strada S. J., Banner R. L., Hersh E. M. Cyclic adenosine 3':5'-monophosphate phosphodiesterase. Distinct forms in human lymphocytes and monocytes. J Biol Chem. 1976 Aug 25;251(16):4922–4929. [PubMed] [Google Scholar]
  44. Watson J. The influence of intracellular levels of cyclic nucleotides on cell proliferation and the induction of antibody synthesis. J Exp Med. 1975 Jan 1;141(1):97–111. doi: 10.1084/jem.141.1.97. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Yang T. J., Vas S. I. Growth inhibitory effects of adenosine 3',5'-monophosphate on mouse leukemia L-5178-Y-R cells in culture. Experientia. 1971 Apr 15;27(4):442–444. doi: 10.1007/BF02137301. [DOI] [PubMed] [Google Scholar]

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