Journal of Neuro-Oncology

, Volume 9, Issue 1, pp 17–28

Relationship between of blood flow, glucose metabolism, protein synthesis, glucose and ATP content in experimentally-induced glioma (RG12.2) of rat brain

  • G. Mies
  • W. Paschen
  • G. Ebhardt
  • K. A. Hossmann
Laboratory Investigation

Summary

In experimental RGl 2.2 glioma of rat brain, local blood flow, glucose utilization, protein synthesis, glucose and ATP content were measured by means of triple tracer autoradiography and bioluminescence technique, respectively, to determine hemodynamic and metabolic thresholds for local tumor energy failure. Perfusion thresholds were estimated at tumor blood flow values of 69.0 ± 0.1 ml/100 g/min (estimate ± standard error) and of 69 ± 7.1 ml/100 g/min for the beginning of the decline in regional ATP and glucose content, respectively. Metabolic thresholds were derived at tumor glucose utilization values of 70.6 ± 8.3 µ mol/100 g/min for reduced protein synthesis, of 55.0 ± 0.2 µmol/100 g/min for the decrease in glucose content, and 34.7 ± 4.7 µmol/100 g/min for decline in ATP content. Our results suggest that blood flow limits glucose supply to tumor tissue at much higher flow rates than in normal brain which, in turn, is associated with a decrease in tumor glucose utilization. A reduction and not an increase in tumor glucose availability could be a more appropriate strategy for the induction of energy failure in tumors.

Key words

brain tumor triple tracer autoradiography blood flow glucose metabolism protein synthesis energy state thresholds 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Lantos PL: Chemical induction of tumors in the central nervous system. In: Thomas DGT and Graham DI (eds) Brain Tumors: Scientific Basis Clinical Investigation and Current Therapy. Butterworths, London, 1980, pp 85–108Google Scholar
  2. 2.
    Copeland DD, Vogel FS, Bigner DD: The induction of intracranial neoplasms by the inoculation of avian sarcoma virus in perinatal and adult rats. J Neuropathol Exp Neurol 34: 340–358, 1975Google Scholar
  3. 3.
    Ushio Y, Chernik NL, Shapiro WR, Posner J: Metastatic tumor of the brain: development of an experimental model. Ann Neurol 2: 20–29, 1977Google Scholar
  4. 4.
    Mennel HD, Ivancovic S: Experimentelle Erzeugung von Tumoren des Nervensystems. In: Grundmann E (ed) Handbuch der allgemeinen Pathologie, Bd IV, Tumoren III, Springer, Berlin, Heidelberg, New York, 1975, pp 33–122Google Scholar
  5. 5.
    Benda PH, Someda K, Messer J, Sweet WH: Morphological and immunochemical studies of rat glial tumors and clonal strains propagated in culture. J Neurosurg 34: 310–323, 1971Google Scholar
  6. 6.
    Hossmann K-A, Mies G, Paschen W, Csiba L, Bodsch W, Rapin JR, Le Poncin-Lafitte M, Takahashi K: Multiparametric imaging of blood flow, and metabolism after middle cerebral artery occlusion in cats. J Cereb Blood Flow Metab 5: 97–107, 1985Google Scholar
  7. 7.
    Sakurada O, Kennedy C, Jehle J, Brown JD, Carbin GL, Sokoloff L: Measurement of local cerebral blood flow with iodo(14C)antipyrine. Am J Physiol 234: H59-H66, 1978Google Scholar
  8. 8.
    Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurada O, Shinohara M: The 14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 28: 299–306, 1977Google Scholar
  9. 9.
    Smith CB, Crane AM, Kadekaro M, Agranoff B, Sokoloff L: Stimulation of protein synthesis and glucose utilization in the hypoglossal nucleus induced by axotomy. J Neurosc 4: 2489–2496, 1984Google Scholar
  10. 10.
    Mies G, Niebuhr I, Hossmann K-A: Simultaneous measurement of blood flow and glucose metabolism by autoradiographic techniques. Stroke 12: 581–588, 1981Google Scholar
  11. 11.
    Mies G, Bodsch W, Paschen W, Hossmann K-A: Tripletracer autoradiography of cerebral blood flow, glucose utilization, and protein synthesis in rat brain. J Cereb Blood Flow Metab 6: 59–70, 1986Google Scholar
  12. 12.
    Kogure K, Alonso OF: A pictorial representation of endogenous brain ATP by a bioluminescent method. Brain Res 154: 273–284, 1978Google Scholar
  13. 13.
    Paschen W, Niebuhr I, Hossmann K-A: A bioluminescent method for the demonstration of regional glucose distribution in brain slices. J Neurochem 36: 513–517, 1981Google Scholar
  14. 14.
    Paschen W, Hossmann K-A, Kerckhoff W vd: Regional assessment of energy-producing metabolism following prolonged complete ischemia of cat brain. J Cereb Blood Flow Metab 3: 321–329, 1983Google Scholar
  15. 15.
    Neter J, Wassermann W, Kutner MH: Applied linear statistical models. Homewood, Illinois, Richard D. Irwin, Inc. 1985Google Scholar
  16. 16.
    Goochee C, Rasband W, Sokoloff L: Computerized densitometry and color coding of 14C-deoxyglucose autoradiographs. Ann Neurol 7: 359–370, 1980Google Scholar
  17. 17.
    Paschen W, Mies G, Kloiber O, Hossmann K-A: Regional quantitative determination of lactate in brain sections. J Cereb Blood Flow Metab 5: 465–468, 1985Google Scholar
  18. 18.
    Sachs L: Angewandte Statistik: Anwendung statistischer Methoden. Berlin, Springer-Verlag, 1984Google Scholar
  19. 19.
    Hürter T, Mennel HD: Experimental brain tumors and edema in rats. I. Histology and cytology of tumors. Acta Neuropathol 55: 105–111, 1981Google Scholar
  20. 20.
    Mennel HD: Transplantation of tumours of the central nervous system induced by resorptive carcinogens. 1. Histological investigation of transplanted tumours of the central nervous system. Neurosurg Rev 1: 123–313, 1978Google Scholar
  21. 21.
    Dickens F, Simer F: Metabolism of normal and brain tumor tissue: II. The respiratory quotient and the relationship of respiration to glycolysis. Biochem J 24: 1031–1326, 1930Google Scholar
  22. 22.
    Warburg O: Über den Stoffwechsel von Tumoren. Springer, Berlin, 1926Google Scholar
  23. 23.
    Warburg O: Metabolism of tumours. London: Constable & Co., 1930Google Scholar
  24. 24.
    Victor J, Wolf A: Metabolism of brain tumors. In: Zabriskie EG, Frantz AN, Hare CC (eds) Tumours of the central nervous system. An Investigation of the most recent advances. Proc Res Nerv Ment Dis 16: 44–58, 1937.Google Scholar
  25. 25.
    Heller IH, Elliott KAC: The metabolism of normal brain and human gliomas in relation to cell type and density. Canad J Biochem Physiol 33: 395–403, 1955Google Scholar
  26. 26.
    Mahaley MS: The in vitro respiration of normal brain and brain tumors. Cancer Res 26: 195–197, 1966Google Scholar
  27. 27.
    Kvamme E: Glycolysis and respiration in Ehrlich ascites tumor cells. I. Phosphate metabolism in relation to glycolysis and the Crabtree effect. Acta Physiol Scand 42: 204–218, 1958Google Scholar
  28. 28.
    Ibsen KH, Coe EL, McKee RW: Energy compensation in the Crabtree effect with Ehrlich ascites cancer cells. Nature (Lond.) 183: 1471, 1959Google Scholar
  29. 29.
    Quastel JH, Bickis IJ: Metabolism of normal and neoplasms in vitro. Nature (Lond.) 183: 281–289, 1959Google Scholar
  30. 30.
    Ibsen KH: The Crabtree effect: a review. Cancer Res 21: 829–841, 1961Google Scholar
  31. 31.
    Kirsch WM: Substrates of glycolysis in intracranial tumors and analogous normal tissue. Neurology 9: 432–439, 1959Google Scholar
  32. 32.
    Kirsch WM: Substrates of glycolysis in intracranial tumors during complete ischemia. Cancer Res 25: 432–439, 1965Google Scholar
  33. 33.
    Kirsch WM, Schulz D, Leitner JN: The effect of prolonged ischemia upon regional energy reserves in the experimental glioblastoma. Cancer Res 27: 2212–2220, 1967Google Scholar
  34. 34.
    Hossmann K-A, Niebuhr I, Tamura M: Local cerebral blood flow and glucose consumption of rats with experimental gliomas. J Cereb Blood Flow Metab 2: 25–32, 1982Google Scholar
  35. 35.
    Yamada K, Hayakawa T, Ushio Y, Arita N, Kato A, Mogami H: Regional blood flow and capillary permeability in ethyl-nitrosourea induced rat glioma. J Neurosurg 55: 922–928, 1981Google Scholar
  36. 36.
    Yamada K, Ushio Y, Hayakawa T, Arita N, Yamada N, Mogami H: Effects of methylprednisolone on peritumoral brain edema. J Neurosurg 59: 612–619, 1983Google Scholar
  37. 37.
    Blasberg RG, Gazendam J, Shapiro WR, Shinohara WR, Patlak CS, Fenstermacher JD: Clinical implications of quantitative autoradiographic measurements of regional blood flow, capillary permeability and glucose utilization in metastatic brain tumor model. In: Hildebrand J and Gangji D (eds) Treatment of Neoplastic Lesions of the Nervous System. Oxford, Pergamon, 1983, pp 135–141Google Scholar
  38. 38.
    Groothuis D, Blasberg RG, Molnar P, Bigner D, Fenstermacher JD: Regional blood flow in avian sarcoma virus (ASV)-induced brain tumors. Neurology 33: 686–696, 1983Google Scholar
  39. 39.
    Kato A, Diksic M, Yamamoto YL, Feindel W: Quantification of glucose utilization in an experimental brain tumor model by the deoxyglucose model. J Cereb Blood Flow Metab 5: 108–114, 1985Google Scholar
  40. 40.
    Ito M, Lammertsma AA, Wise RJS, Bernardi S, Frackowiak RSJ, Heather JD, McKenzie CG, Thomas DGT, Jones T: Measurement of regional cerebral blood flow and oxygen utilization in patients with cerebral tumours using 15O and positron emission tomography: Analytical techniques and preliminary results. Neuroradiology 23: 63–74, 1982Google Scholar
  41. 41.
    Di Chiro G, DeLaPaz RL, Brooks RA, Sokoloff L, Kornblith PL, Smith BH, Patronas NJ, Kufta CV, Kessler RM, Johnston GS, Manning RG, Wolf AP: Glucose utilization of cerebral gliomas measured by [18F] fluoro-deoxyglucose and positron emission tomography. Neurology 32: 1323–1329, 1982Google Scholar
  42. 42.
    Blasberg RG, Molnar P, Horowitz M, Kornblith R, Pleasants R, Fenstermacher JD: Regional blood flow in RT-9 brain tumors. J Neurosurg 58: 863–873, 1983Google Scholar
  43. 43.
    Rhodes CG, Wise RJS, Gibbs JM, Frackowiak RSJ, Hatazawa J, Palmer AJ, Thomas DGT, Jones T: In vivo disturbance of the oxidative metabolism of glucose in human cerebral gliomas. Ann Neurol 14: 614–626, 1983Google Scholar
  44. 44.
    Leenders KL, Beaney RP, Brooks DJ, Lammertsma AA, Heather JD, McKenzie CG: Dexamethasone treatment of brain tumor patients: effect on regional cerebral blood flow, blood volume and oxygen utilization. Neurology 35: 1610–1616, 1985Google Scholar
  45. 45.
    Herholz K, Ziffling P, Staffen W, Pawlik G, Wagner R, Wienhard K, Heiss W-D: Uncoupling of hexose transport and phosphorylation in human gliomas demonstrated by PET. Eur J Cancer Clin Oncol 24: 1139–1150, 1988Google Scholar
  46. 46.
    Keller K, Lange K, Noske W: D-glucose transport in cultured cells of neuronal origin: the membrane as possible control point of glucose utilization. J Neurochem 36: 1012–1017, 1981Google Scholar
  47. 47.
    Hossmann K-A, Mies G, Paschen W, Szabo L, Dolan E, Wechsler W: Regional metabolism of experimental gliomas. Acta Neuropathol 69: 139–147, 1986Google Scholar
  48. 48.
    von Ardenne M, Reitnauer PG, Rhode K, Westmeyer H: In vivo pH-Messungen in Krebs-Mikrometastasen bei optimierter Übersäuerung. Z Naturforsch 24: 1610–1619, 1969Google Scholar
  49. 49.
    Smith CB, Deibler GE, Eng N, Schmidt K, Sokoloff L: Measurement of local cerebral protein synthesis in vivo: influence of recycling of amino acids derived from protein degradations. Proc Natl Acad Sci 85: 9341–9345, 1988Google Scholar

Copyright information

© Kluwer Academic Publishers 1990

Authors and Affiliations

  • G. Mies
    • 1
  • W. Paschen
    • 1
  • G. Ebhardt
    • 2
  • K. A. Hossmann
    • 1
  1. 1.Sektion Neuropathologie der Krankenanstalten KölnMax-Planck-Institut für neurologische Forschung Abteilung für experimentelle NeurologieKölnFRG
  2. 2.Sektion Neuropathologie der Krankenanstalten KölnInstitut für PathologieKölnFRG
  3. 3.Abteilung für experimentelle NeurologieMax-Planck-Institut für neurologische ForschungKöln 91FRG

Personalised recommendations