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. 2000 May 18;82(12):2007–2014. doi: 10.1054/bjoc.2000.1144

Effects of nicotinamide and carbogen on tumour oxygenation, blood flow, energetics and blood glucose levels

S P Robinson 1, F A Howe 1, M Stubbs 1, J R Griffiths 1
PMCID: PMC2363252  PMID: 10864210

Abstract

Both host carbogen (95% oxygen/5% carbon dioxide) breathing and nicotinamide administration enhance tumour radiotherapeutic response and are being re-evaluated in the clinic. Non-invasive magnetic resonance imaging (MRI) and 31P magnetic resonance spectroscopy (MRS) methods have been used to give information on the effects of nicotinamide alone and in combination with host carbogen breathing on transplanted rat GH3 prolactinomas. Gradient recalled echo (GRE) MRI, sensitive to blood oxygenation changes, and spin echo (SE) MRI, sensitive to perfusion/flow, showed large signal intensity increases with carbogen breathing. Nicotinamide, thought to act by suppressing the transient closure of small blood vessels that cause intermittent tumour hypoxia, induced a small increase in blood oxygenation but no detectable change in perfusion/flow. Carbogen combined with nicotinamide was no more effective than carbogen alone. Both carbogen and nicotinamide caused significant increases in the nucleoside triphosphate/inorganic phosphate (βNTP/P i) ratio, implying that the tumour cells normally receive sub-optimal substrate supply, and is consistent with either increased glycolysis and/or a switch to more oxidative metabolism. The most striking observation was the marked increase in blood glucose (twofold) induced by both nicotinamide and carbogen. Whether this may play a role in tumour radiosensitivity has yet to be determined. Copyright 2000 Cancer Research Campaign© 2000 Cancer Research Campaign

Keywords: carbogen, nicotinamide, hydralazine, oxygenation, blood flow, MRI

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Selected References

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  1. Al-Hallaq H. A., River J. N., Zamora M., Oikawa H., Karczmar G. S. Correlation of magnetic resonance and oxygen microelectrode measurements of carbogen-induced changes in tumor oxygenation. Int J Radiat Oncol Biol Phys. 1998 Apr 1;41(1):151–159. doi: 10.1016/s0360-3016(98)00038-8. [DOI] [PubMed] [Google Scholar]
  2. Ammon H. P., Estler C. J. The effect of nicotinic acid on glycolytic carbohydrate breakdown in the liver. Life Sci. 1967 Mar 15;6(6):641–647. doi: 10.1016/0024-3205(67)90101-4. [DOI] [PubMed] [Google Scholar]
  3. Bates S., Yetkin Z., Jesmanowicz A., Hyde J. S., Bandettini P. A., Estkowski L., Haughton V. M. Artifacts in functional magnetic resonance imaging from gaseous oxygen. J Magn Reson Imaging. 1995 Jul-Aug;5(4):443–445. doi: 10.1002/jmri.1880050413. [DOI] [PubMed] [Google Scholar]
  4. Bernier J., Denekamp J., Rojas A., Trovò M., Horiot J. C., Hamers H., Antognoni P., Dahl O., Richaud P., Kaanders J. ARCON: accelerated radiotherapy with carbogen and nicotinamide in non small cell lung cancer: a phase I/II study by the EORTC. Radiother Oncol. 1999 Aug;52(2):149–156. doi: 10.1016/s0167-8140(99)00106-1. [DOI] [PubMed] [Google Scholar]
  5. Bhujwalla Z. M., Tozer G. M., Field S. B., Maxwell R. J., Griffiths J. R. The energy metabolism of RIF-1 tumours following hydralazine. Radiother Oncol. 1990 Nov;19(3):281–291. doi: 10.1016/0167-8140(90)90155-p. [DOI] [PubMed] [Google Scholar]
  6. Biaglow J. E., Manevich Y., Leeper D., Chance B., Dewhirst M. W., Jenkins W. T., Tuttle S. W., Wroblewski K., Glickson J. D., Stevens C. MIBG inhibits respiration: potential for radio- and hyperthermic sensitization. Int J Radiat Oncol Biol Phys. 1998 Nov 1;42(4):871–876. doi: 10.1016/s0360-3016(98)00334-4. [DOI] [PubMed] [Google Scholar]
  7. Braun R. D., Lanzen J. L., Dewhirst M. W. Fourier analysis of fluctuations of oxygen tension and blood flow in R3230Ac tumors and muscle in rats. Am J Physiol. 1999 Aug;277(2 Pt 2):H551–H568. doi: 10.1152/ajpheart.1999.277.2.H551. [DOI] [PubMed] [Google Scholar]
  8. Brown S. L., Ewing J. R., Kolozsvary A., Butt S., Cao Y., Kim J. H. Magnetic resonance imaging of perfusion in rat cerebral 9L tumor after nicotinamide administration. Int J Radiat Oncol Biol Phys. 1999 Feb 1;43(3):627–633. doi: 10.1016/s0360-3016(98)00422-2. [DOI] [PubMed] [Google Scholar]
  9. Chaplin D. J., Horsman M. R., Aoki D. S. Nicotinamide, Fluosol DA and Carbogen: a strategy to reoxygenate acutely and chronically hypoxic cells in vivo. Br J Cancer. 1991 Jan;63(1):109–113. doi: 10.1038/bjc.1991.22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chaplin D. J., Horsman M. R., Trotter M. J. Effect of nicotinamide on the microregional heterogeneity of oxygen delivery within a murine tumor. J Natl Cancer Inst. 1990 Apr 18;82(8):672–676. doi: 10.1093/jnci/82.8.672. [DOI] [PubMed] [Google Scholar]
  11. Chaplin D. J., Olive P. L., Durand R. E. Intermittent blood flow in a murine tumor: radiobiological effects. Cancer Res. 1987 Jan 15;47(2):597–601. [PubMed] [Google Scholar]
  12. Dewhirst M. W., Vinuya R. Z., Ong E. T., Klitzman B., Rosner G., Secomb T. W., Gross J. F. Effects of bradykinin on the hemodynamics of tumor and granulating normal tissue microvasculature. Radiat Res. 1992 Jun;130(3):345–354. [PubMed] [Google Scholar]
  13. Dunn J. F., Frostick S., Adams G. E., Stratford I. J., Howells N., Hogan G., Radda G. K. Induction of tumour hypoxia by a vasoactive agent. A combined NMR and radiobiological study. FEBS Lett. 1989 Jun 5;249(2):343–347. doi: 10.1016/0014-5793(89)80655-6. [DOI] [PubMed] [Google Scholar]
  14. Dunn J. F., Swartz H. M. Blood oxygenation. Heterogeneity of hypoxic tissues monitored using bold MR imaging. Adv Exp Med Biol. 1997;428:645–650. [PubMed] [Google Scholar]
  15. Duyn J. H., Moonen C. T., van Yperen G. H., de Boer R. W., Luyten P. R. Inflow versus deoxyhemoglobin effects in BOLD functional MRI using gradient echoes at 1.5 T. NMR Biomed. 1994 Mar;7(1-2):83–88. doi: 10.1002/nbm.1940070113. [DOI] [PubMed] [Google Scholar]
  16. Eddy H. A., Casarett G. W. Development of the vascular system in the hamster malignant neurilemmoma. Microvasc Res. 1973 Jul;6(1):63–82. doi: 10.1016/0026-2862(73)90007-1. [DOI] [PubMed] [Google Scholar]
  17. GRAY L. H., CONGER A. D., EBERT M., HORNSEY S., SCOTT O. C. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol. 1953 Dec;26(312):638–648. doi: 10.1259/0007-1285-26-312-638. [DOI] [PubMed] [Google Scholar]
  18. Griffiths J. R., Taylor N. J., Howe F. A., Saunders M. I., Robinson S. P., Hoskin P. J., Powell M. E., Thoumine M., Caine L. A., Baddeley H. The response of human tumors to carbogen breathing, monitored by Gradient-Recalled Echo Magnetic Resonance Imaging. Int J Radiat Oncol Biol Phys. 1997 Oct 1;39(3):697–701. doi: 10.1016/s0360-3016(97)00326-x. [DOI] [PubMed] [Google Scholar]
  19. Horsman M. R., Brown J. M., Hirst V. K., Lemmon M. J., Wood P. J., Dunphy E. P., Overgaard J. Mechanism of action of the selective tumor radiosensitizer nicotinamide. Int J Radiat Oncol Biol Phys. 1988 Sep;15(3):685–690. doi: 10.1016/0360-3016(88)90312-4. [DOI] [PubMed] [Google Scholar]
  20. Horsman M. R., Chaplin D. J., Brown J. M. Radiosensitization by nicotinamide in vivo: a greater enhancement of tumor damage compared to that of normal tissues. Radiat Res. 1987 Mar;109(3):479–489. [PubMed] [Google Scholar]
  21. Horsman M. R. Nicotinamide and other benzamide analogs as agents for overcoming hypoxic cell radiation resistance in tumours. A review. Acta Oncol. 1995;34(5):571–587. doi: 10.3109/02841869509094031. [DOI] [PubMed] [Google Scholar]
  22. Hoskin P. J., Saunders M. I., Phillips H., Cladd H., Powell M. E., Goodchild K., Stratford M. R., Rojas A. Carbogen and nicotinamide in the treatment of bladder cancer with radical radiotherapy. Br J Cancer. 1997;76(2):260–263. doi: 10.1038/bjc.1997.372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Howe F. A., Robinson S. P., Griffiths J. R. Modification of tumour perfusion and oxygenation monitored by gradient recalled echo MRI and 31P MRS. NMR Biomed. 1996 Aug;9(5):208–216. doi: 10.1002/(SICI)1099-1492(199608)9:5<208::AID-NBM418>3.0.CO;2-H. [DOI] [PubMed] [Google Scholar]
  24. Howe F. A., Robinson S. P., Rodrigues L. M., Griffiths J. R. Flow and oxygenation dependent (FLOOD) contrast MR imaging to monitor the response of rat tumors to carbogen breathing. Magn Reson Imaging. 1999 Nov;17(9):1307–1318. doi: 10.1016/s0730-725x(99)00089-2. [DOI] [PubMed] [Google Scholar]
  25. Jirtle R. L. Chemical modification of tumour blood flow. Int J Hyperthermia. 1988 Jul-Aug;4(4):355–371. doi: 10.3109/02656738809016490. [DOI] [PubMed] [Google Scholar]
  26. Kaanders J. H., Pop L. A., Marres H. A., Liefers J., van den Hoogen F. J., van Daal W. A., van der Kogel A. J. Accelerated radiotherapy with carbogen and nicotinamide (ARCON) for laryngeal cancer. Radiother Oncol. 1998 Aug;48(2):115–122. doi: 10.1016/s0167-8140(98)00043-7. [DOI] [PubMed] [Google Scholar]
  27. Kimura H., Braun R. D., Ong E. T., Hsu R., Secomb T. W., Papahadjopoulos D., Hong K., Dewhirst M. W. Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res. 1996 Dec 1;56(23):5522–5528. [PubMed] [Google Scholar]
  28. Kjellen E., Joiner M. C., Collier J. M., Johns H., Rojas A. A therapeutic benefit from combining normobaric carbogen or oxygen with nicotinamide in fractionated X-ray treatments. Radiother Oncol. 1991 Oct;22(2):81–91. doi: 10.1016/0167-8140(91)90002-x. [DOI] [PubMed] [Google Scholar]
  29. Menke H., Vaupel P. Effect of injectable or inhalational anesthetics and of neuroleptic, neuroleptanalgesic, and sedative agents on tumor blood flow. Radiat Res. 1988 Apr;114(1):64–76. [PubMed] [Google Scholar]
  30. Moreno F. J., Sánchez-Urrutia L., Medina J. M., Sánchez-Medina F., Mayor F. Stimulation of phosphoenolpyruvate carboxykinase (guanosine triphosphate) activity by low concentrations of circulating glucose in perfused rat liver. Biochem J. 1975 Jul;150(1):51–58. doi: 10.1042/bj1500051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Ogawa S., Lee T. M., Nayak A. S., Glynn P. Oxygenation-sensitive contrast in magnetic resonance image of rodent brain at high magnetic fields. Magn Reson Med. 1990 Apr;14(1):68–78. doi: 10.1002/mrm.1910140108. [DOI] [PubMed] [Google Scholar]
  32. Oikawa H., al-Hallaq H. A., Lewis M. Z., River J. N., Kovar D. A., Karczmar G. S. Spectroscopic imaging of the water resonance with short repetition time to study tumor response to hyperoxia. Magn Reson Med. 1997 Jul;38(1):27–32. doi: 10.1002/mrm.1910380106. [DOI] [PubMed] [Google Scholar]
  33. Ojugo A. S., McSheehy P. M., McIntyre D. J., McCoy C., Stubbs M., Leach M. O., Judson I. R., Griffiths J. R. Measurement of the extracellular pH of solid tumours in mice by magnetic resonance spectroscopy: a comparison of exogenous (19)F and (31)P probes. NMR Biomed. 1999 Dec;12(8):495–504. doi: 10.1002/(sici)1099-1492(199912)12:8<495::aid-nbm594>3.0.co;2-k. [DOI] [PubMed] [Google Scholar]
  34. Okunieff P., Kallinowski F., Vaupel P., Neuringer L. J. Effects of hydralazine-induced vasodilation on the energy metabolism of murine tumors studied by in vivo 31P-nuclear magnetic resonance spectroscopy. J Natl Cancer Inst. 1988 Jul 20;80(10):745–750. doi: 10.1093/jnci/80.10.745. [DOI] [PubMed] [Google Scholar]
  35. Prysor-Jones R. A., Jenkins J. S. Effect of bromocriptine on DNA synthesis, growth and hormone secretion of spontaneous pituitary tumours in the rat. J Endocrinol. 1981 Mar;88(3):463–469. doi: 10.1677/joe.0.0880463. [DOI] [PubMed] [Google Scholar]
  36. Robinson S. P., Collingridge D. R., Howe F. A., Rodrigues L. M., Chaplin D. J., Griffiths J. R. Tumour response to hypercapnia and hyperoxia monitored by FLOOD magnetic resonance imaging. NMR Biomed. 1999 Apr;12(2):98–106. doi: 10.1002/(sici)1099-1492(199904)12:2<98::aid-nbm556>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
  37. Robinson S. P., Howe F. A., Griffiths J. R. Noninvasive monitoring of carbogen-induced changes in tumor blood flow and oxygenation by functional magnetic resonance imaging. Int J Radiat Oncol Biol Phys. 1995 Nov 1;33(4):855–859. doi: 10.1016/0360-3016(95)00072-1. [DOI] [PubMed] [Google Scholar]
  38. Robinson S. P., Rodrigues L. M., Ojugo A. S., McSheehy P. M., Howe F. A., Griffiths J. R. The response to carbogen breathing in experimental tumour models monitored by gradient-recalled echo magnetic resonance imaging. Br J Cancer. 1997;75(7):1000–1006. doi: 10.1038/bjc.1997.172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Robinson S. P., van den Boogaart A., Maxwell R. J., Griffiths J. R., Hamilton E., Waterton J. C. 31P-magnetic resonance spectroscopy and 2H-magnetic resonance imaging studies of a panel of early-generation transplanted murine tumour models. Br J Cancer. 1998 Jun;77(11):1752–1760. doi: 10.1038/bjc.1998.293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Sansom J. M., Wood P. J. 31P MRS of tumour metabolism in anaesthetized vs conscious mice. NMR Biomed. 1994 Jun;7(4):167–171. doi: 10.1002/nbm.1940070403. [DOI] [PubMed] [Google Scholar]
  41. Sauer L. A., Stayman J. W., 3rd, Dauchy R. T. Amino acid, glucose, and lactic acid utilization in vivo by rat tumors. Cancer Res. 1982 Oct;42(10):4090–4097. [PubMed] [Google Scholar]
  42. Stubbs M., Robinson S. P., Rodrigues L. M., Parkins C. S., Collingridge D. R., Griffiths J. R. The effects of host carbogen (95% oxygen/5% carbon dioxide) breathing on metabolic characteristics of Morris hepatoma 9618a. Br J Cancer. 1998 Dec;78(11):1449–1456. doi: 10.1038/bjc.1998.706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. THOMLINSON R. H., GRAY L. H. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer. 1955 Dec;9(4):539–549. doi: 10.1038/bjc.1955.55. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Tozer G. M., Griffiths J. R. The contribution made by cell death and oxygenation to 31P MRS observations of tumour energy metabolism. NMR Biomed. 1992 Sep-Oct;5(5):279–289. doi: 10.1002/nbm.1940050515. [DOI] [PubMed] [Google Scholar]
  45. Vaupel P., Kallinowski F., Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res. 1989 Dec 1;49(23):6449–6465. [PubMed] [Google Scholar]
  46. Wood P. J., Counsell C. J., Bremner J. C., Horsman M. R., Adams G. E. The measurement of radiosensitizer-induced changes in mouse tumor metabolism by 31P magnetic resonance spectroscopy. Int J Radiat Oncol Biol Phys. 1991 Feb;20(2):291–294. doi: 10.1016/0360-3016(91)90107-f. [DOI] [PubMed] [Google Scholar]
  47. Yamaura H., Matsuzawa T. Tumor regrowth after irradiation; an experimental approach. Int J Radiat Biol Relat Stud Phys Chem Med. 1979 Mar;35(3):201–219. doi: 10.1080/09553007914550241. [DOI] [PubMed] [Google Scholar]
  48. van den Boogaart A., Howe F. A., Rodrigues L. M., Stubbs M., Griffiths J. R. In vivo 31P MRS: absolute concentrations, signal-to-noise and prior knowledge. NMR Biomed. 1995 Apr;8(2):87–93. doi: 10.1002/nbm.1940080207. [DOI] [PubMed] [Google Scholar]

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