Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1991 Oct;64(4):683–688. doi: 10.1038/bjc.1991.381

The potential for prazosin and calcitonin gene-related peptide (CGRP) in causing hypoxia in tumours.

I A Burney 1, R J Maxwell 1, J R Griffiths 1, S B Field 1
PMCID: PMC1977707  PMID: 1911217

Abstract

Using 31P NMR spectroscopy, changes in tumour metabolic status were studied in a transplanted rat fibrosarcoma following the administration of vasodilators. Mean Arterial Blood Pressure (MABP) was monitored simultaneously. Two vasodilators were studied, prazosin and CGRP, which altered the NMR parameters Pi/sigma P, beta NTP,Pi, PCr/Pi and PME/Pi in a dose dependent manner. There was a good correlation between the various NMR parameters; for analysis, Pi/sigma P was used for convenience. With increasing doses of vasodilator, Pi/sigma P increased and the MABP decreased. Reduction in pHNMR showed a correlation with decreasing MABP following the administration of prazosin but not after CGRP. Both prazosin and CGRP produced changes in 31P NMR spectra consistent with a reduction in tumour blood flow. The results for prazosin and CGRP were comparable and showed a 15-20% increase in Pi/sigma P for a 20% reduction in MABP. These results were compared with those from hydralazine. With hydralazine an acceptable reduction in blood pressure (up to approximately 25%) has little effect and may even alter NMR parameters consistent with an increase in blood flow, a reduction of approximately 40% is required for a significant decrease in flow. Both prazosin and CGRP are shown to be far more effective than hydralazine in causing tumour hypoxia at a clinically acceptable reduction in blood pressure. CGRP may be the more suitable for clinical use because of its short half life, its capability to achieve controlled hypotension and the relatively few side effects associated with its use.

Full text

PDF
683

Selected References

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

  1. ABLAD B. A study of the mechanism of the hemodynamic effects of hydralazine in man. Acta Pharmacol Toxicol (Copenh) 1963;20(Suppl 1):1–53. [PubMed] [Google Scholar]
  2. Babbs C. F., DeWitt D. P., Voorhees W. D., McCaw J. S., Chan R. C. Theoretical feasibility of vasodilator-enhanced local tumor heating. Eur J Cancer Clin Oncol. 1982 Nov;18(11):1137–1146. doi: 10.1016/0277-5379(82)90095-5. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Bhujwalla Z. M., Tozer G. M., Field S. B., Proctor E., Busza A., Williams S. R. The combined measurement of blood flow and metabolism in RIF-1 tumours in vivo. A study using H2 flow and 31P NMR spectroscopy. NMR Biomed. 1990 Aug;3(4):178–183. doi: 10.1002/nbm.1940030406. [DOI] [PubMed] [Google Scholar]
  5. Brain S. D., Williams T. J., Tippins J. R., Morris H. R., MacIntyre I. Calcitonin gene-related peptide is a potent vasodilator. Nature. 1985 Jan 3;313(5997):54–56. doi: 10.1038/313054a0. [DOI] [PubMed] [Google Scholar]
  6. Bremner J. C., Stratford I. J., Bowler J., Adams G. E. Bioreductive drugs and the selective induction of tumour hypoxia. Br J Cancer. 1990 May;61(5):717–721. doi: 10.1038/bjc.1990.161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chan R. C., Babbs C. F., Vetter R. J., Lamar C. H. Abnormal response of tumor vasculature to vasoactive drugs. J Natl Cancer Inst. 1984 Jan;72(1):145–150. doi: 10.1093/jnci/72.1.145. [DOI] [PubMed] [Google Scholar]
  8. Chaplin D. J., Acker B. The effect of hydralazine on the tumor cytotoxicity of the hypoxic cell cytotoxin RSU-1069: evidence for therapeutic gain. Int J Radiat Oncol Biol Phys. 1987 Apr;13(4):579–585. doi: 10.1016/0360-3016(87)90075-7. [DOI] [PubMed] [Google Scholar]
  9. Cullen B. M., Walker H. C. The effect of several different anaesthetics on the blood pressure and heart rate of the mouse and on the radiation response of the mouse sarcoma RIF-1. Int J Radiat Biol Relat Stud Phys Chem Med. 1985 Nov;48(5):761–771. doi: 10.1080/09553008514551861. [DOI] [PubMed] [Google Scholar]
  10. Dart A. M., Riemersma R. A., Schömig A., Ungar A. Metabolic requirements for release of endogenous noradrenaline during myocardial ischaemia and anoxia. Br J Pharmacol. 1987 Jan;90(1):43–50. doi: 10.1111/j.1476-5381.1987.tb16823.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Evelhoch J. L., Sapareto S. A., Nussbaum G. H., Ackerman J. J. Correlations between 31P NMR spectroscopy and 15O perfusion measurements in the RIF-1 murine tumor in vivo. Radiat Res. 1986 Apr;106(1):122–131. [PubMed] [Google Scholar]
  12. Fisher L. A., Kikkawa D. O., Rivier J. E., Amara S. G., Evans R. M., Rosenfeld M. G., Vale W. W., Brown M. R. Stimulation of noradrenergic sympathetic outflow by calcitonin gene-related peptide. Nature. 1983 Oct 6;305(5934):534–536. doi: 10.1038/305534a0. [DOI] [PubMed] [Google Scholar]
  13. Gerweck L. E., Nygaard T. G., Burlett M. Response of cells to hyperthermia under acute and chronic hypoxic conditions. Cancer Res. 1979 Mar;39(3):966–972. [PubMed] [Google Scholar]
  14. Horsman M. R., Christensen K. L., Overgaard J. Hydralazine-induced enhancement of hyperthermic damage in a C3H mammary carcinoma in vivo. Int J Hyperthermia. 1989 Mar-Apr;5(2):123–136. doi: 10.3109/02656738909140442. [DOI] [PubMed] [Google Scholar]
  15. Kalmus J., Okunieff P., Vaupel P. Dose-dependent effects of hydralazine on microcirculatory function and hyperthermic response of murine FSall tumors. Cancer Res. 1990 Jan 1;50(1):15–19. [PubMed] [Google Scholar]
  16. Lundberg J. M., Franco-Cereceda A., Hua X., Hökfelt T., Fischer J. A. Co-existence of substance P and calcitonin gene-related peptide-like immunoreactivities in sensory nerves in relation to cardiovascular and bronchoconstrictor effects of capsaicin. Eur J Pharmacol. 1985 Feb 5;108(3):315–319. doi: 10.1016/0014-2999(85)90456-x. [DOI] [PubMed] [Google Scholar]
  17. Maekawa K., Liang C. S., Tsui A., Chen B. T., Kawashima S. Vasodilative effect of hydralazine in awake dogs: the roles of prostaglandins and the sympathetic nervous system. Circulation. 1984 Nov;70(5):908–916. doi: 10.1161/01.cir.70.5.908. [DOI] [PubMed] [Google Scholar]
  18. Morris H. R., Panico M., Etienne T., Tippins J., Girgis S. I., MacIntyre I. Isolation and characterization of human calcitonin gene-related peptide. Nature. 1984 Apr 19;308(5961):746–748. doi: 10.1038/308746a0. [DOI] [PubMed] [Google Scholar]
  19. Mueller-Klieser W., Schaefer C., Walenta S., Rofstad E. K., Fenton B. M., Sutherland R. M. Assessment of tumor energy and oxygenation status by bioluminescence, nuclear magnetic resonance spectroscopy, and cryospectrophotometry. Cancer Res. 1990 Mar 15;50(6):1681–1685. [PubMed] [Google Scholar]
  20. Okunieff P., Walsh C. S., Vaupel P., Kallinowski F., Hitzig B. M., Neuringer L. J., Suit H. D. Effects of hydralazine on in vivo tumor energy metabolism, hematopoietic radiation sensitivity, and cardiovascular parameters. Int J Radiat Oncol Biol Phys. 1989 May;16(5):1145–1148. doi: 10.1016/0360-3016(89)90270-8. [DOI] [PubMed] [Google Scholar]
  21. Reinhold H. S., Endrich B. Tumour microcirculation as a target for hyperthermia. Int J Hyperthermia. 1986 Apr-Jun;2(2):111–137. doi: 10.3109/02656738609012389. [DOI] [PubMed] [Google Scholar]
  22. Rofstad E. K., DeMuth P., Fenton B. M., Ceckler T. L., Sutherland R. M. 31P NMR spectroscopy and HbO2 cryospectrophotometry in prediction of tumor radioresistance caused by hypoxia. Int J Radiat Oncol Biol Phys. 1989 Apr;16(4):919–923. doi: 10.1016/0360-3016(89)90887-0. [DOI] [PubMed] [Google Scholar]
  23. Rosenfeld M. G., Mermod J. J., Amara S. G., Swanson L. W., Sawchenko P. E., Rivier J., Vale W. W., Evans R. M. Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing. Nature. 1983 Jul 14;304(5922):129–135. doi: 10.1038/304129a0. [DOI] [PubMed] [Google Scholar]
  24. Rowell N. P., Flower M. A., McCready V. R., Cronin B., Horwich A. The effects of single dose oral hydralazine on blood flow through human lung tumours. Radiother Oncol. 1990 Aug;18(4):283–292. doi: 10.1016/0167-8140(90)90108-9. [DOI] [PubMed] [Google Scholar]
  25. Skolleborg K. C., Grönbech J. E., Grong K., Abyholm F. E., Lekven J. Distribution of cardiac output during pentobarbital versus midazolam/fentanyl/fluanisone anaesthesia in the rat. Lab Anim. 1990 Jul;24(3):221–227. doi: 10.1258/002367790780866100. [DOI] [PubMed] [Google Scholar]
  26. Stanaszek W. F., Kellerman D., Brogden R. N., Romankiewicz J. A. Prazosin update. A review of its pharmacological properties and therapeutic use in hypertension and congestive heart failure. Drugs. 1983 Apr;25(4):339–384. doi: 10.2165/00003495-198325040-00002. [DOI] [PubMed] [Google Scholar]
  27. Stratford I. J., Adams G. E., Godden J., Howells N. Induction of tumour hypoxia post-irradiation: a method for increasing the sensitizing efficiency of misonidazole and RSU 1069 in vivo. Int J Radiat Biol. 1989 Mar;55(3):411–422. doi: 10.1080/09553008914550451. [DOI] [PubMed] [Google Scholar]
  28. Struthers A. D., Brown M. J., Macdonald D. W., Beacham J. L., Stevenson J. C., Morris H. R., MacIntyre I. Human calcitonin gene related peptide: a potent endogenous vasodilator in man. Clin Sci (Lond) 1986 Apr;70(4):389–393. doi: 10.1042/cs0700389. [DOI] [PubMed] [Google Scholar]
  29. Tozer G. M., Bhujwalla Z. M., Griffiths J. R., Maxwell R. J. Phosphorus-31 magnetic resonance spectroscopy and blood perfusion of the RIF-1 tumor following X-irradiation. Int J Radiat Oncol Biol Phys. 1989 Jan;16(1):155–164. doi: 10.1016/0360-3016(89)90023-0. [DOI] [PubMed] [Google Scholar]
  30. Tozer G. M., Maxwell R. J., Griffiths J. R., Pham P. Modification of the 31P magnetic resonance spectra of a rat tumour using vasodilators and its relationship to hypotension. Br J Cancer. 1990 Oct;62(4):553–560. doi: 10.1038/bjc.1990.329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Tozer G. M., Morris C. C. Blood flow and blood volume in a transplanted rat fibrosarcoma: comparison with various normal tissues. Radiother Oncol. 1990 Feb;17(2):153–165. doi: 10.1016/0167-8140(90)90103-4. [DOI] [PubMed] [Google Scholar]
  32. Trotter M. J., Acker B. D., Chaplin D. J. Histological evidence for nonperfused vasculature in a murine tumor following hydralazine administration. Int J Radiat Oncol Biol Phys. 1989 Oct;17(4):785–789. doi: 10.1016/0360-3016(89)90067-9. [DOI] [PubMed] [Google Scholar]
  33. Vaupel P., Okunieff P., Kallinowski F., Neuringer L. J. Correlations between 31P-NMR spectroscopy and tissue O2 tension measurements in a murine fibrosarcoma. Radiat Res. 1989 Dec;120(3):477–493. [PubMed] [Google Scholar]
  34. Voorhees W. D., 3rd, Babbs C. F. Hydralazine-enhanced selective heating of transmissible venereal tumor implants in dogs. Eur J Cancer Clin Oncol. 1982 Oct;18(10):1027–1033. doi: 10.1016/0277-5379(82)90252-8. [DOI] [PubMed] [Google Scholar]
  35. Wiig H., Tveit E., Hultborn R., Reed R. K., Weiss L. Interstitial fluid pressure in DMBA-induced rat mammary tumours. Scand J Clin Lab Invest. 1982 Apr;42(2):159–164. [PubMed] [Google Scholar]
  36. Zaidi M., Breimer L. H., MacIntyre I. Production of calcitonin gene-related peptide from human cancer cells. J Endocrinol. 1989 Oct;123(1):159–165. doi: 10.1677/joe.0.1230159. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES