Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1993 Jul;68(1):41–51. doi: 10.1038/bjc.1993.284

Oral versus intravenous administration of 5-aminolaevulinic acid for photodynamic therapy.

C S Loh 1, A J MacRobert 1, J Bedwell 1, J Regula 1, N Krasner 1, S G Bown 1
PMCID: PMC1968297  PMID: 8318419

Abstract

Endogenously synthesised protoporphyrin IX (PpIX) following the administration of 5-amino-laevulinic acid (ALA) is an effective photosensitiser for photodynamic therapy (PDT). Following intravenous administration, PpIX accumulates predominantly in mucosa of hollow viscera and on light exposure, mucosal ablation results with relative sparing of the submucosa and muscularis layers. Oral administration is effective with ALA in contrast to conventional exogenous photosensitisers such as haematoporphyrin derivative and phthalocyanines. Oral administration of ALA is also simpler, safer, cheaper and more acceptable to patients. We studied the porphyrin sensitisation kinetics profile in the stomach, colon and bladder in normal rats following enterally and parenterally administered ALA using microscopic fluorescence photometric studies of frozen tissue sections. Mucosal cells in all three organs exhibit higher fluorescence levels as compared with underlying smooth muscle following both intravenous and oral administration. Peak concentration were seen 4 h after sensitisation at the highest doses used (200 mg kg-1 i.v., 400 mg kg-1 oral), and slightly earlier with lower doses. The temporal kinetics of both routes of administration were similar although a higher oral dose was required to achieve the same tissue concentration of PpIX. The highest level of fluorescence was achieved in the gastric mucosa and in decreasing levels, colonic and bladder mucosa. A similar degree of mucosal selectivity was achieved in each organ with each route of administration but an oral dose in excess of 40 mg kg-1 was required to achieve measurable PpIX sensitisation. In a pilot clinical study, two patients with inoperable rectal adenocarcinomas were given 30 mg kg-1 and one patient with sigmoid colon carcinoma was given 60 mg kg-1 ALA orally. Serial biopsies of normal and tumour areas were taken over the subsequent 24 h. Fluorescence microscopy of these specimens showed maximum accumulation of PpIX 4 to 6 h after administration of 30 mg kg-1 ALA. There was greater PpIX accumulation in tumour than adjacent normal mucosa in two patients. Preferential PpIX accumulation in tumour was greater in the patient receiving 60 mg kg-1 ALA.

Full text

PDF
41

Images in this article

43Figure 2
on p.43
49Figure 10
on p.49

Selected References

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

  1. Agrez M. V., Wharen R. E., Jr, Anderson R. E., Laws E. R., Jr, Ilstrup D. M., Cortese D. A., Shorter R. G., Lieber M. M. Hematoporphyrin derivative: quantitative uptake in dimethylhydrazine-induced murine colorectal carcinoma. J Surg Oncol. 1983 Nov;24(3):173–176. doi: 10.1002/jso.2930240305. [DOI] [PubMed] [Google Scholar]
  2. BERLIN N. I., NEUBERGER A., SCOTT J. J. The metabolism of delta -aminolaevulic acid. 1. Normal pathways, studied with the aid of 15N. Biochem J. 1956 Sep;64(1):80–90. doi: 10.1042/bj0640080. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bedwell J., MacRobert A. J., Phillips D., Bown S. G. Fluorescence distribution and photodynamic effect of ALA-induced PP IX in the DMH rat colonic tumour model. Br J Cancer. 1992 Jun;65(6):818–824. doi: 10.1038/bjc.1992.175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chan W. S., MacRobert A. J., Phillips D., Hart I. R. Use of charge coupled device camera for imaging of intracellular phthalocyanines. Photochem Photobiol. 1989 Nov;50(5):617–624. doi: 10.1111/j.1751-1097.1989.tb04317.x. [DOI] [PubMed] [Google Scholar]
  5. Dailey H. A., Smith A. Differential interaction of porphyrins used in photoradiation therapy with ferrochelatase. Biochem J. 1984 Oct 15;223(2):441–445. doi: 10.1042/bj2230441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Divaris D. X., Kennedy J. C., Pottier R. H. Phototoxic damage to sebaceous glands and hair follicles of mice after systemic administration of 5-aminolevulinic acid correlates with localized protoporphyrin IX fluorescence. Am J Pathol. 1990 Apr;136(4):891–897. [PMC free article] [PubMed] [Google Scholar]
  7. Edwards S. R., Shanley B. C., Reynoldson J. A. Neuropharmacology of delta-aminolaevulinic acid--I. Effect of acute administration in rodents. Neuropharmacology. 1984 Apr;23(4):477–481. doi: 10.1016/0028-3908(84)90259-4. [DOI] [PubMed] [Google Scholar]
  8. Gomer C. J., Dougherty T. J. Determination of [3H]- and [14C]hematoporphyrin derivative distribution in malignant and normal tissue. Cancer Res. 1979 Jan;39(1):146–151. [PubMed] [Google Scholar]
  9. Kennedy J. C., Pottier R. H., Pross D. C. Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience. J Photochem Photobiol B. 1990 Jun;6(1-2):143–148. doi: 10.1016/1011-1344(90)85083-9. [DOI] [PubMed] [Google Scholar]
  10. Loh C. S., Bedwell J., MacRobert A. J., Krasner N., Phillips D., Bown S. G. Photodynamic therapy of the normal rat stomach: a comparative study between di-sulphonated aluminium phthalocyanine and 5-aminolaevulinic acid. Br J Cancer. 1992 Sep;66(3):452–462. doi: 10.1038/bjc.1992.295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Mustajoki P., Timonen K., Gorchein A., Seppäläinen A. M., Matikainen E., Tenhunen R. Sustained high plasma 5-aminolaevulinic acid concentration in a volunteer: no porphyric symptoms. Eur J Clin Invest. 1992 Jun;22(6):407–411. doi: 10.1111/j.1365-2362.1992.tb01482.x. [DOI] [PubMed] [Google Scholar]
  12. Pope A. J., MacRobert A. J., Phillips D., Bown S. G. The detection of phthalocyanine fluorescence in normal rat bladder wall using sensitive digital imaging microscopy. Br J Cancer. 1991 Nov;64(5):875–879. doi: 10.1038/bjc.1991.417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Razum N., Balchum O. J., Profio A. E., Carstens F. Skin photosensitivity: duration and intensity following intravenous hematoporphyrin derivates, HpD and DHE. Photochem Photobiol. 1987 Nov;46(5):925–928. doi: 10.1111/j.1751-1097.1987.tb04870.x. [DOI] [PubMed] [Google Scholar]
  14. SARDESAI V. M., WALDMAN J., ORTEN J. M. A COMPARATIVE STUDY OF PORPHYRIN BIOSYNTHESIS IN DIFFERENT TISSUES. Blood. 1964 Aug;24:178–186. [PubMed] [Google Scholar]
  15. Schoenfeld N., Epstein O., Lahav M., Mamet R., Shaklai M., Atsmon A. The heme biosynthetic pathway in lymphocytes of patients with malignant lymphoproliferative disorders. Cancer Lett. 1988 Dec 1;43(1-2):43–48. doi: 10.1016/0304-3835(88)90211-x. [DOI] [PubMed] [Google Scholar]
  16. Tralau C. J., Barr H., Sandeman D. R., Barton T., Lewin M. R., Bown S. G. Aluminum sulfonated phthalocyanine distribution in rodent tumors of the colon, brain and pancreas. Photochem Photobiol. 1987 Nov;46(5):777–781. doi: 10.1111/j.1751-1097.1987.tb04847.x. [DOI] [PubMed] [Google Scholar]
  17. Van Hillegersberg R., Van den Berg J. W., Kort W. J., Terpstra O. T., Wilson J. H. Selective accumulation of endogenously produced porphyrins in a liver metastasis model in rats. Gastroenterology. 1992 Aug;103(2):647–651. doi: 10.1016/0016-5085(92)90860-2. [DOI] [PubMed] [Google Scholar]
  18. Weishaupt K. R., Gomer C. J., Dougherty T. J. Identification of singlet oxygen as the cytotoxic agent in photoinactivation of a murine tumor. Cancer Res. 1976 Jul;36(7 Pt 1):2326–2329. [PubMed] [Google Scholar]
  19. el-Sharabasy M. M., el-Waseef A. M., Hafez M. M., Salim S. A. Porphyrin metabolism in some malignant diseases. Br J Cancer. 1992 Mar;65(3):409–412. doi: 10.1038/bjc.1992.83. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES