Skip to main content
Log in

Light fractionated ALA-PDT enhances therapeutic efficacy in vitro; the influence of PpIX concentration and illumination parameters

  • Cummunication
  • Published:
Photochemical & Photobiological Sciences Aims and scope Submit manuscript

Abstract

Light fractionation, with a long dark interval, significantly increases the response to ALA-PDT in pre-clinical models and in non-melanoma skin cancer. We investigated if this increase in efficacy can be replicated in PAM 212 cells in vitro. The results show a significant decrease in cell survival after light fractionation which is dependent on the PpIX concentration and light dose of the first light fraction. This study supports the hypothesis that an underlying cellular mechanism is involved in the response to light fractionation in which a first light fraction leads to sub-lethally damaged cells that are sensitised to a second light fraction 2 hours later. The current study reveals the in vitro circumstances under which we can investigate the cellular pathways involved.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Notes and references

  1. H. C. de Vijlder, H. J. C. M. Sterenborg, H. A. M. Neumann, D. J. Robinson, E. R. M. de Haas, Light fractionation significantly improves the response of superficial basal cell carcinoma to ALA-PDT: five-year follow-up of a randomized, prospective trial, Acta Dermatol. Venerol., 2012, 92, 641–647.

    Article  Google Scholar 

  2. E. Sotiriou, Z. Apalla, E. Chovarda, C. Goussi, A. Trigoni, D. Ioannides, Single vs. fractionated photodynamic therapy for face and scalp actinic keratoses: a randomized, intraindividual comparison trial with 12-month follow-up, J. Eur. Acad. Dermatol. Venereol., 2012, 26, 36–40.

    Article  CAS  Google Scholar 

  3. D. J. Robinson, H. S. de Bruijn, W. M. Star, H. J. C. M. Sterenborg, Dose and timing of the first light fraction in two fold illumination schemes for topical ALA-mediated photodynamic therapy of hairless mouse skin, Photochem. Photobiol., 2003, 77, 319–323.

    Article  CAS  Google Scholar 

  4. N. van der Veen, H. L. L. M. van Leengoed, W. M. Star, In vivo fluorescence kinetics and photodynamic therapy using 5-aminolevulinic acid-induced porphyrin: increased damage after multiple irradiations, Br. J. Cancer, 1994, 70, 867–872.

    Article  Google Scholar 

  5. H. S. de Bruijn, N. van der Veen, D. J. Robinson, W. M. Star, Improvement of systemic 5-aminolevulinic acid-based photodynamic therapy in vivo using light fractionation with a 75 minute interval, Cancer Res., 1999, 59, 901–904.

    PubMed  Google Scholar 

  6. N. van der Veen, K. M. Hebeda, H. S. de Bruijn, W. M. Star, Photodynamic effectiveness and vasoconstriction in hairless mouse skin after topical 5-aminolevulinic acid and single or two-fold illumination, Photochem. Photobiol., 1999, 70, 921–929.

    Article  Google Scholar 

  7. N. van der Veen, H. S. de Bruijn, W. M. Star, Photobleaching during and re-appearance after photodynamic therapy of topical ALA-induced fluorescence in UVB-treated mouse skin, Int. J. Cancer, 1997, 72, 110–118.

    Article  Google Scholar 

  8. A. Orenstein, G. Kostenich, Z. Malik, The kinetics of protoporphyrin fluorescence during ALA-PDT in human malignant skin tumors, Cancer Lett., 1997, 120, 229–234.

    Article  CAS  Google Scholar 

  9. C. af Klintenberg, A. M. K. Enejder, I. Wang, S. Andersson-Engels, S. Svanberg, K. Svandberg, Kinetic fluorescence studies of 5-aminolaevulinic acid-induced protoporphyrin IX accumulation in basal cell carcinomas, J. Photochem. Photobiol., B, 1999, 49, 120–128.

    Article  Google Scholar 

  10. H. S. de Bruijn, B. Kruijt, A. van der Ploeg-van den Heuvel, H. J. C. M. Sterenborg, D. J. Robinson, Increase in protoporphyrin IX after 5-aminolevulinic based photodynamic therapy is due to local resynthesis, Photochem. Photobiol. Sci., 2007, 6, 857–864.

    Article  Google Scholar 

  11. D. J. Robinson, H. S. de Bruijn, J. de Wolf, H. J. C. M. Sterenborg, W. M. Star, Topical 5-aminolevulinic acid-photodynamic therapy of hairless mouse skin using two-fold illumination schemes: PpIX fluorescence kinetics, photobleaching and biological effect, Photochem. Photobiol., 2000, 72, 794–802.

    Article  CAS  Google Scholar 

  12. H. S. de Bruijn, A. van der Ploeg–van den Heuvel, H. J. C. M. Sterenborg, D. J. Robinson, Fractionated illumination after topical application of 5-aminolevulinic acid on normal skin of hairless mice: the influence of the dark interval, J. Photochem. Photobiol., B, 2006, 85, 184–190.

    Article  Google Scholar 

  13. T. A. Middelburg, F. van Zaane, H. S. de Bruijn, A. van der Ploeg–van den Heuvel, H. J. C. M. Sterenborg, H. A. M. Neumann, E. R. M. de Haas, D. J. Robinson, Fractionated illumination at low fluence rate photodynamic therapy in mice, Photochem. Photobiol., 2010, 86, 1140–1146.

    Article  CAS  Google Scholar 

  14. S. H. Yuspa, P. Hawley-Nelson, B. Koehler, J. R. Stanley, A survey of transformation markers in differentiating epidermal cell lines, Cancer Res., 1980, 40, 4694–4703.

    CAS  PubMed  Google Scholar 

  15. C. Perotti, H. Fukuda, G. DiVenosa, A. J. MacRobert, A. Batlle, A. Casas, Porphyrin synthesis from ALA derivatives for photodynamic therapy, in vitro and in vivo studies, Br. J. Cancer, 2004, 90, 1660–1665.

    Article  CAS  Google Scholar 

  16. Z. Ji, G. Yang, V. Vasovic, B. Cunderlikova, Z. Suo, J. M. Nesland, Q. Peng, Subcellular localization pattern of protoporphyrin IX is an important determinant for its photodynamic efficiency of human carcinoma and normal cell lines, J. Photochem. Photobiol., B, 2006, 84, 213–220.

    Article  CAS  Google Scholar 

  17. M. J. Niedre, A. J. Secord, M. S. Patterson, B. C. Wilson, In vitro tests of the validity of singlet oxygen luminescence measurements as a dose metric in photodynamic therapy, Cancer Res., 2003, 63, 7986–7994.

    CAS  PubMed  Google Scholar 

  18. S. Correa Garcia, A. Casas, C. Perotti, A. Batlle, M. Bermudez Morreti, Mechanistic studies on δ-aminolevulinic acid uptake and efflux in a mammary adenocarcinoma cell line, Br. J. Cancer, 2003, 89, 173–177.

    Article  CAS  Google Scholar 

  19. B. J. Wilson, M. Olivo, G. Singh, Subcellular localization of photofrin and aminolevulinic acid and photodynamic cross-resistance in vitro in radiation-induced fibrosarcoma cells sensitive or resistant to photofrin mediated photodynamic therapy, Photochem. Photobiol., 1997, 65, 166–176.

    Article  CAS  Google Scholar 

  20. D. Grebenova, K. Kuzelova, K. Smetana, M. Pluskalova, H. Cajthamlova, I. Marinov, O. Fuchs, J. Soucek, P. Jarolim, Z. Hrkal, Mitochondrial and endoplasmic reticulum stress-induced apoptotic pathways are activated by 5-aminolevulinic acid-based photodynamic therapy in HL60 leukemia cells, J. Photochem. Photobiol., B, 2003, 69, 71–85.

    Article  CAS  Google Scholar 

  21. J. Moan, On the diffusion length of singlet oxygen in cells and tissues, J. Photochem. Photobiol., B, 1990, 6, 343–344.

    Article  CAS  Google Scholar 

  22. S. K. Bisland, E. A. Goebel, N. S. Hassanali, C. Johnson, B. C. Wilson, Increased expression of mitochondrial benzodiazepine receptors following low-level light treatment facilitates enhanced protoporphyrin IX production in glioma-derived cells in vitro, Lasers Surg. Med., 2007, 39, 678–684.

    Article  CAS  Google Scholar 

  23. T. Kriska, W. Korytowski, A. W. Girotti, Role of mitochondrial cardiolipin peroxidation in apoptotic photokilling of 5-aminolevulinate-treated tumor cells, Arch. Biochem. Biophys., 2005, 433, 435–446.

    Article  CAS  Google Scholar 

  24. N. L. Oleinick, R. L. Morris, I. Belinchenko, The role of apoptosis in response to photodynamic therapy: what where why and how, Photochem. Photobiol. Sci., 2002, 1, 1–21.

    Article  CAS  Google Scholar 

  25. D. Kessel, M. G. Vicente, J. J. Reiners, Initiation of apoptosis and autophagy by photodynamic therapy, Lasers Surg. Med., 2006, 38, 482–488.

    Article  Google Scholar 

  26. E. Buyaert, M. Dewaele, P. Agostinis, Molecular effectors of multiple cell death pathways initiated by photodynamic therapy, Biochim. Biophys. Acta, 2007, 1776, 86–107.

    Google Scholar 

  27. H. T. Ji, L. T. Chen, Y. H. Lin, H. F. Chien, C. H. Chen, 5-ALA mediated photodynamic therapy induces autophagic cell death via the AMP-activated protein kinase, Mol. Cancer, 2010, 9, 91.

    Article  Google Scholar 

  28. I. Coupienne, S. Bontems, M. Dewaele, N. Rubio, Y. Habraken, S. Fulda, P. Agostinis, J. Piette, NF-kappaB inhibition improves the sensitivity of human glioblastoma cells to 5-aminolevulinic acid-based photodynamic therapy, Biochem. Pharmacol., 2011, 81, 606–616.

    Article  CAS  Google Scholar 

  29. E. R. M. de Haas, H. S. de Bruijn, H. J. C. M. Sterenborg, H. A. M. Neumann, D. J. Robinson, Microscopic distribution of protoporphyrin IX (PpIX) fluorescence in superficial basal cell carcinoma during light fractionated aminolevulinic acid photodynamic therapy, Acta Dermatol. Venerol., 2008, 88, 547–554.

    Google Scholar 

  30. H. S. de Bruijn, E. R. M. de Haas, K. M. Hebeda, A. van der Ploeg–van den Heuvel, H. J. C. M. Sterenborg, H. A. M. Neumann, D. J. Robinson, Light fractionation does not enhance the efficacy of methyl 5-aminolevulinate mediated photodynamic therapy in normal mouse skin, Photochem. Photobiol. Sci., 2007, 6, 1325–1331.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Dominic J. Robinson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

de Bruijn, H.S., Casas, A.G., Di Venosa, G. et al. Light fractionated ALA-PDT enhances therapeutic efficacy in vitro; the influence of PpIX concentration and illumination parameters. Photochem Photobiol Sci 12, 241–245 (2013). https://doi.org/10.1039/c2pp25287b

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1039/c2pp25287b

Navigation