Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Jun;80(7):998–1004. doi: 10.1038/sj.bjc.6690454

δ-Aminolaevulinic acid-induced photodynamic therapy inhibits protoporphyrin IX biosynthesis and reduces subsequent treatment efficacy in vitro

S L Gibson 1, J J Havens 1, M L Nguyen 1, R Hilf 1
PMCID: PMC2363048  PMID: 10362107

Abstract

Recently, considerable interest has been given to photodynamic therapy of cancer using δ-aminolaevulinic acid to induce protoporphyrin IX as the cell photosensitizer. One advantage of this modality is that protoporphyrin IX is cleared from tissue within 24 h after δ-aminolaevulinic acid administration. This could allow for multiple treatment regimens because of little concern regarding the accumulation of the photosensitizer in normal tissues. However, the haem biosynthetic pathway would have to be fully functional after the first course of therapy to allow for subsequent treatments. Photosensitization of cultured R3230AC rat mammary adenocarcinoma cells with δ-aminolaevulinic acid-induced protoporphyrin IX resulted in the inhibition of porphobilinogen deaminase, an enzyme in the haem biosynthetic pathway, and a concomitant decrease in protoporphyrin IX levels. Cultured R3230AC cells exposed to 0.5 mM δ-aminolaevulinic acid for 27 h accumulated 6.07 × 10−16 mol of protoporphyrin IX per cell and had a porphobilinogen deaminase activity of 0.046 fmol uroporphyrin per 30 min per cell. Cells cultured under the same incubation conditions but exposed to 30 mJ cm−2 irradiation after a 3-h incubation with δ-aminolaevulinic acid showed a significant reduction in protoporphyrin IX, 2.28 × 10−16 mol per cell, and an 80% reduction in porphobilinogen deaminase activity to 0.0088 fmol uroporphyrin per 30 min per cell. Similar effects were evident in irradiated cells incubated with δ-aminolaevulinic acid immediately after, or following a 24 h interval, post-irradiation. There was little gain in efficacy from a second treatment regimen applied within 24 h of the initial treatment, probably a result of initial metabolic damage leading to reduced levels of protoporphyrin IX. These findings suggest that a correlation may exist between the δ-aminolaevulinic acid induction of porphobilinogen deaminase activity and the increase in intracellular protoporphyrin IX accumulation. © 1999 Cancer Research Campaign

Keywords: δ-aminolaevulinic acid, protoporphyrin IX, porphobilinogen deaminase, photodynamic therapy

Full Text

The Full Text of this article is available as a PDF (111.7 KB).

Selected References

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

  1. Ades I. Z. Heme production in animal tissues: the regulation of biogenesis of delta-aminolevulinate synthase. Int J Biochem. 1990;22(6):565–578. doi: 10.1016/0020-711x(90)90032-x. [DOI] [PubMed] [Google Scholar]
  2. Batlle A. M. Porphyrins, porphyrias, cancer and photodynamic therapy--a model for carcinogenesis. J Photochem Photobiol B. 1993 Sep;20(1):5–22. doi: 10.1016/1011-1344(93)80127-u. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Fan K. F., Hopper C., Speight P. M., Buonaccorsi G. A., Bown S. G. Photodynamic therapy using mTHPC for malignant disease in the oral cavity. Int J Cancer. 1997 Sep 26;73(1):25–32. doi: 10.1002/(sici)1097-0215(19970926)73:1<25::aid-ijc5>3.0.co;2-3. [DOI] [PubMed] [Google Scholar]
  5. Fisher A. M., Murphree A. L., Gomer C. J. Clinical and preclinical photodynamic therapy. Lasers Surg Med. 1995;17(1):2–31. doi: 10.1002/lsm.1900170103. [DOI] [PubMed] [Google Scholar]
  6. Gibson S. L., Cupriks D. J., Havens J. J., Nguyen M. L., Hilf R. A regulatory role for porphobilinogen deaminase (PBGD) in delta-aminolaevulinic acid (delta-ALA)-induced photosensitization? Br J Cancer. 1998;77(2):235–242. doi: 10.1038/bjc.1998.39. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gibson S. L., Nguyen M. L., Foster T. H., White G., Hilf R. Efficacy of photodynamic therapy on original and recurrent rat mammary tumors. Photochem Photobiol. 1995 Feb;61(2):196–199. doi: 10.1111/j.1751-1097.1995.tb03960.x. [DOI] [PubMed] [Google Scholar]
  8. Gomer C. J. Preclinical examination of first and second generation photosensitizers used in photodynamic therapy. Photochem Photobiol. 1991 Dec;54(6):1093–1107. doi: 10.1111/j.1751-1097.1991.tb02133.x. [DOI] [PubMed] [Google Scholar]
  9. Grandchamp B., Phung N., Grelier M., Nordmann Y. The spectrophotometric determination of uroporphyrinogen I synthetase activity. Clin Chim Acta. 1976 Jul 1;70(1):113–118. doi: 10.1016/0009-8981(76)90011-5. [DOI] [PubMed] [Google Scholar]
  10. HILF R., MICHEL I., BELL C., FREEMAN J. J., BORMAN A. BIOCHEMICAL AND MORPHOLOGIC PROPERTIES OF A NEW LACTATING MAMMARY TUMOR LINE IN THE RAT. Cancer Res. 1965 Apr;25:286–299. [PubMed] [Google Scholar]
  11. He D., Behar S., Nomura N., Sassa S., Lim H. W. The effect of ALA and radiation on porphyrin/heme biosynthesis in endothelial cells. Photochem Photobiol. 1995 Jun;61(6):656–661. doi: 10.1111/j.1751-1097.1995.tb09884.x. [DOI] [PubMed] [Google Scholar]
  12. He D., Sassa S., Lim H. W. Effect of UVA and blue light on porphyrin biosynthesis in epidermal cells. Photochem Photobiol. 1993 May;57(5):825–829. doi: 10.1111/j.1751-1097.1993.tb09218.x. [DOI] [PubMed] [Google Scholar]
  13. Healey J. F., Bonkowsky H. L., Sinclair P. R., Sinclair J. F. Conversion of 5-aminolaevulinate into haem by liver homogenates. Comparison of rat and chick embryo. Biochem J. 1981 Sep 15;198(3):595–604. doi: 10.1042/bj1980595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hissin P. J., Hilf R. Effects of insulin in vivo and in vitro on amino acid transport into cells from the R3230AC mammary adenocarcinoma and their relationship to tumor growth. Cancer Res. 1978 Nov;38(11 Pt 1):3646–3655. [PubMed] [Google Scholar]
  15. Kennedy J. C., Pottier R. H. Endogenous protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy. J Photochem Photobiol B. 1992 Jul 30;14(4):275–292. doi: 10.1016/1011-1344(92)85108-7. [DOI] [PubMed] [Google Scholar]
  16. Kriegmair M., Baumgartner R., Knüchel R., Stepp H., Hofstädter F., Hofstetter A. Detection of early bladder cancer by 5-aminolevulinic acid induced porphyrin fluorescence. J Urol. 1996 Jan;155(1):105–110. [PubMed] [Google Scholar]
  17. Malik Z., Kostenich G., Roitman L., Ehrenberg B., Orenstein A. Topical application of 5-aminolevulinic acid, DMSO and EDTA: protoporphyrin IX accumulation in skin and tumours of mice. J Photochem Photobiol B. 1995 Jun;28(3):213–218. doi: 10.1016/1011-1344(95)07117-k. [DOI] [PubMed] [Google Scholar]
  18. Malik Z., Lugaci H. Destruction of erythroleukaemic cells by photoactivation of endogenous porphyrins. Br J Cancer. 1987 Nov;56(5):589–595. doi: 10.1038/bjc.1987.246. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Moan J., Bech O., Gaullier J. M., Stokke T., Steen H. B., Ma L. W., Berg K. Protoporphyrin IX accumulation in cells treated with 5-aminolevulinic acid: dependence on cell density, cell size and cell cycle. Int J Cancer. 1998 Jan 5;75(1):134–139. doi: 10.1002/(sici)1097-0215(19980105)75:1<134::aid-ijc20>3.0.co;2-f. [DOI] [PubMed] [Google Scholar]
  20. Pandey R. K., Potter W. R., Meunier I., Sumlin A. B., Smith K. M. Evaluation of new benzoporphyrin derivatives with enhanced PDT efficacy. Photochem Photobiol. 1995 Oct;62(4):764–768. doi: 10.1111/j.1751-1097.1995.tb08727.x. [DOI] [PubMed] [Google Scholar]
  21. Peng Q., Berg K., Moan J., Kongshaug M., Nesland J. M. 5-Aminolevulinic acid-based photodynamic therapy: principles and experimental research. Photochem Photobiol. 1997 Feb;65(2):235–251. doi: 10.1111/j.1751-1097.1997.tb08549.x. [DOI] [PubMed] [Google Scholar]
  22. Rosenthal D. I., Glatstein E. Clinical applications of photodynamic therapy. Ann Med. 1994 Dec;26(6):405–409. doi: 10.3109/07853899409148361. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Washbrook R., Fukuda H., Battle A., Riley P. Stimulation of tetrapyrrole synthesis in mammalian epithelial cells in culture by exposure to aminolaevulinic acid. Br J Cancer. 1997;75(3):381–387. doi: 10.1038/bjc.1997.62. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Wyld L., Burn J. L., Reed M. W., Brown N. J. Factors affecting aminolaevulinic acid-induced generation of protoporphyrin IX. Br J Cancer. 1997;76(6):705–712. doi: 10.1038/bjc.1997.450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. van Hillegersberg R., Kort W. J., Wilson J. H. Current status of photodynamic therapy in oncology. Drugs. 1994 Oct;48(4):510–527. doi: 10.2165/00003495-199448040-00003. [DOI] [PubMed] [Google Scholar]
  27. van der Veen N., van Leengoed H. L., Star W. M. In vivo fluorescence kinetics and photodynamic therapy using 5-aminolaevulinic acid-induced porphyrin: increased damage after multiple irradiations. Br J Cancer. 1994 Nov;70(5):867–872. doi: 10.1038/bjc.1994.412. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES