Journal of Cancer Research and Clinical Oncology

, Volume 134, Issue 8, pp 841–849 | Cite as

Enhancement of methyl-aminolevulinate photodynamic therapy by iron chelation with CP94: an in vitro investigation and clinical dose-escalating safety study for the treatment of nodular basal cell carcinoma

Original Paper

Abstract

Purpose

Methyl-aminolevulinate (MAL) photodynamic therapy (PDT) is a cancer therapy that combines the selective accumulation of a photosensitizer in tumor tissue with visible light (and tissue oxygen) to produce reactive oxygen species. This results in cellular damage and ablation of tumor tissue. Combining iron chelators with MAL has the potential to increase the accumulation of the photosensitizer protoporphyrin IX (PpIX) by reducing its bioconversion to heme. This paper investigates this method of enhancement both in vitro and for the first time clinically for the treatment of nodular basal cell carcinoma (BCC).

Methods

Enhancement of MAL-induced PpIX accumulation by the iron chelator CP94 was quantified fluorometrically in human cultured cells (including three dermatological cell types). An open, dose-escalating, pilot study was then conducted in patients with nodular BCC, to determine the safety of this pharmacological modification.

Results

Large enhancements in PpIX accumulation were observed in the cultured cells when co-incubated with the iron chelator CP94. Clinically the addition of CP94 was found to be feasible and safe. In addition greater reductions in tumor depth were observed in the CP94 co-incubated tumors.

Conclusion

Iron chelation by CP94 is an effective enhancer of MAL-induced PpIX accumulation in vitro. This method of enhancement was safely applied to a clinical PDT protocol with no unexpected adverse effects reported. Although the clinical investigation was only intended to be a small pilot to assess safety, enhancements in tumor clearance were observed both clinically and histologically when CP94 was included in the photosensitizing cream.

Keywords

Carcinoma Basal cell 1,2-Diethyl-3-hydroxypyridin-4-one (CP94) Iron chelating agents Metvix® Methyl-aminolevulinate (MAL) Photochemotherapy 

Notes

Acknowledgments

This work was supported by the Duchy Health Charity Limited. The authors thank Professor Hider (Kings College London) for kindly providing the CP94 used in this study.

References

  1. Bech O, Phillips D, Moan J, MacRobert AJ (1997) A hydroxypyridinone (CP94) enhances protoporphyrin IX formation in 5-aminolaevulinic acid treated cells. J Photochem Photobiol B 41:136–144PubMedCrossRefGoogle Scholar
  2. Berg K, Anholt H, Bech O, Moan J (1996) The influence of iron chelators on the accumulation of protoporphyrin IX in 5-aminolaevulinic acid-treated cells. Br J Cancer 74:688–697PubMedGoogle Scholar
  3. Bremner JC, Adams GE, Pearson JK, Sansom JM, Stratford IJ, Bedwell J, Bown SG, MacRobert AJ, Phillips D (1992) Increasing the effect of photodynamic therapy on the RIF-1 murine sarcoma, using the bioreductive drugs RSU1069 and RB6145. Br J Cancer 66:1070–1076PubMedGoogle Scholar
  4. Casas A, Batlle AM, Butler AR, Robertson D, Brown EH, MacRobert A, Riley PA (1999) Comparative effect of ALA derivatives on protoporphyrin IX production in human and rat skin organ cultures. Br J Cancer 80:1525–1532PubMedCrossRefGoogle Scholar
  5. Chang SC, MacRobert AJ, Porter JB, Bown SG (1997) The efficacy of an iron chelator (CP94) in increasing cellular protoporphyrin IX following intravesical 5-aminolaevulinic acid administration: an in vivo study. J Photochem Photobiol B 38:114–122PubMedCrossRefGoogle Scholar
  6. Choudry K, Brooke RC, Farrar W, Rhodes LE (2003) The effect of an iron chelating agent on protoporphyrin IX levels and phototoxicity in topical 5-aminolaevulinic acid photodynamic therapy. Br J Dermatol 149:124–130PubMedCrossRefGoogle Scholar
  7. Curnow A, McIlroy BW, Postle-Hacon MJ, Porter JB, MacRobert AJ, Bown SG (1998) Enhancement of 5-aminolaevulinic acid-induced photodynamic therapy in normal rat colon using hydroxypyridinone iron-chelating agents. Br J Cancer 78:1278–1282PubMedGoogle Scholar
  8. Curnow A, McIlroy BW, Postle-Hacon MJ, MacRobert AJ, Bown SG (1999) Light dose fractionation to enhance photodynamic therapy using 5-aminolevulinic acid in the normal rat colon. Photochem Photobiol 69:71–76PubMedCrossRefGoogle Scholar
  9. Dougherty TJ, Kaufman JE, Goldfarb A, Weishaupt KR, Boyle D, Mittleman A (1978) Photoradiation therapy for the treatment of malignant tumors. Cancer Res 38:2628–2635PubMedGoogle Scholar
  10. el Sharabasy MM, el Waseef AM, Hafez MM, Salim SA (1992) Porphyrin metabolism in some malignant diseases. Br J Cancer 65:409–412PubMedGoogle Scholar
  11. Fijan S, Honigsmann H, Ortel B (1995) Photodynamic therapy of epithelial skin tumours using delta-aminolaevulinic acid and desferrioxamine. Br J Dermatol 133:282–288PubMedCrossRefGoogle Scholar
  12. Gibbs SL, Chen B, O’hara JA, Hoopes PJ, Hasan T, Pogue BW (2006) Protoporphyrin IX Level correlates with number of mitochondria, but increases in production correlate with tumor cell size. Photochem Photobiol 82:1334–1341PubMedCrossRefGoogle Scholar
  13. Hanania J, Malik Z (1992) The effect of EDTA and serum on endogenous porphyrin accumulation and photodynamic sensitization of human K562 leukemic cells. Cancer Lett 65:127–131PubMedCrossRefGoogle Scholar
  14. Henderson BW, Dougherty TJ (1992) How does photodynamic therapy work? Photochem Photobiol 55:145–157PubMedCrossRefGoogle Scholar
  15. Hoyes KP, Porter JB (1993) Subcellular distribution of desferrioxamine and hydroxypyridin-4-one chelators in K562 cells affects chelation of intracellular iron pools. Br J Haematol 85:393–400PubMedCrossRefGoogle Scholar
  16. Ibbotson SH, Jong C, Lesar A, Ferguson JS, Padgett M, O’Dwyer M, Barnetson R, Ferguson J (2006) Characteristics of 5-aminolaevulinic acid-induced protoporphyrin IX fluorescence in human skin in vivo. Photodermatol Photoimmunol Photomed 22:105–110PubMedCrossRefGoogle Scholar
  17. Juzeniene A, Juzenas P, Bronshtein I, Vorobey A, Moan J (2006) The influence of temperature on photodynamic cell killing in vitro with 5-aminolevulinic acid. J Photochem Photobiol B 84:161–166PubMedCrossRefGoogle Scholar
  18. Krieg RC, Messmann H, Rauch J, Seeger S, Knuechel R (2002) Metabolic characterization of tumor cell-specific protoporphyrin IX accumulation after exposure to 5-aminolevulinic acid in human colonic cells. Photochem Photobiol 76:518–525PubMedCrossRefGoogle Scholar
  19. Liu HF, Xu SZ, Zhang CR (2004) Influence of CaNa2 EDTA on topical 5-aminolaevulinic acid photodynamic therapy. Chin Med J (Engl) 117:922–926Google Scholar
  20. Lopez RF, Bentley MV, Delgado-Charro MB, Salomon D, van den BH, Lange N, Guy RH (2003) Enhanced delivery of 5-aminolevulinic acid esters by iontophoresis in vitro. Photochem Photobiol 77:304–308Google Scholar
  21. Malik Z, Lugaci H (1987) Destruction of erythroleukaemic cells by photoactivation of endogenous porphyrins. Br J Cancer 56:589–595PubMedGoogle Scholar
  22. Messmann H, Mlkvy P, Buonaccorsi G, Davies CL, MacRobert AJ, Bown SG (1995) Enhancement of photodynamic therapy with 5-aminolaevulinic acid-induced porphyrin photosensitisation in normal rat colon by threshold and light fractionation studies. Br J Cancer 72:589–594PubMedGoogle Scholar
  23. Morton CA, Brown SB, Collins S, Ibbotson S, Jenkinson H, Kurwa H, Langmack K, McKenna K, Moseley H, Pearse AD, Stringer M, Taylor DK, Wong G, Rhodes LE (2002) Guidelines for topical photodynamic therapy: report of a workshop of the British Photodermatology Group. Br J Dermatol 146:552–567PubMedCrossRefGoogle Scholar
  24. Orenstein A, Kostenich G, Roitman L, Shechtman Y, Kopolovic Y, Ehrenberg B, Malik Z (1996) A comparative study of tissue distribution and photodynamic therapy selectivity of chlorin e6, Photofrin II and ALA-induced protoporphyrin IX in a colon carcinoma model. Br J Cancer 73:937–944PubMedGoogle Scholar
  25. Orenstein A, Kostenich G, Kopolovic Y, Babushkina T, Malik Z (1999) Enhancement of ALA-PDT damage by IR-induced hyperthermia on a colon carcinoma model. Photochem Photobiol 69:703–707PubMedGoogle Scholar
  26. Ortel B, Tanew A, Honigsmann H (1993) Lethal photosensitization by endogenous porphyrins of PAM cells-modification by desferrioxamine. J Photochem Photobiol B 17:273–278PubMedCrossRefGoogle Scholar
  27. Peng Q, Warloe T, Berg K, Moan J, Kongshaug M, Giercksky KE, Nesland JM (1997) 5-Aminolevulinic acid-based photodynamic therapy. Clinical research and future challenges. Cancer 79:2282–2308PubMedCrossRefGoogle Scholar
  28. Peng Q, Warloe T, Moan J, Godal A, Apricena F, Giercksky KE, Nesland JM (2001) Antitumor effect of 5-aminolevulinic acid-mediated photodynamic therapy can be enhanced by the use of a low dose of photofrin in human tumor xenografts. Cancer Res 61:5824–5832PubMedGoogle Scholar
  29. Pye A, Curnow A (2007) Direct comparison of aminolevulinic-acid and methyl-aminolevulinate-dervived-protoporphyrin IX accumulations potentiated by desferrioxamine or the novel hydroxypyridinone iron chelator CP94 in cultured human cells. Photochem Photobiol 83:766–773PubMedCrossRefGoogle Scholar
  30. Rhodes LE, De Rie M, Enstrom Y, Groves R, Morken T, Goulden V, Wong GA, Grob JJ, Varma S, Wolf P (2004) Photodynamic therapy using topical methyl aminolevulinate vs surgery for nodular basal cell carcinoma: results of a multicenter randomized prospective trial. Arch Dermatol 140:17–23PubMedCrossRefGoogle Scholar
  31. Robinson DJ, de Bruijn HS, van der Veen N, Stringer MR, Brown SB, Star WM (1998) Fluorescence photobleaching of ALA-induced protoporphyrin IX during photodynamic therapy of normal hairless mouse skin: the effect of light dose and irradiance and the resulting biological effect. Photochem Photobiol 67:140–149PubMedGoogle Scholar
  32. Smith AG, Clothier B, Francis JE, Gibbs AH, De Matteis F, Hider RC (1997) Protoporphyria induced by the orally active iron chelator 1,2-diethyl-3-hydroxypyridin-4-one in C57BL/10ScSn mice. Blood 89:1045–1051PubMedGoogle Scholar
  33. Soler AM, Warloe T, Berner A, Giercksky KE (2001) A follow-up study of recurrence and cosmesis in completely responding superficial and nodular basal cell carcinomas treated with methyl 5-aminolaevulinate-based photodynamic therapy alone and with prior curettage. Br J Dermatol 145:467–471PubMedCrossRefGoogle Scholar
  34. Svanberg K, Andersson T, Killander D, Wang I, Stenram U, Andersson-Engels S, Berg R, Johansson J, Svanberg S (1994) Photodynamic therapy of non-melanoma malignant tumours of the skin using topical delta-amino levulinic acid sensitization and laser irradiation. Br J Dermatol 130:743–751PubMedCrossRefGoogle Scholar
  35. Wang I, Bendsoe N, Klinteberg CA, Enejder AM, Andersson-Engels S, Svanberg S, Svanberg K (2001) Photodynamic therapy vs. cryosurgery of basal cell carcinomas: results of a phase III clinical trial. Br J Dermatol 144:832–840PubMedCrossRefGoogle Scholar
  36. Wu SM, Ren QG, Zhou MO, Wei Y, Chen JY (2003) Photodynamic effects of 5-aminolevulinic acid and its hexylester on several cell lines. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai) 35:655–660Google Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Cornwall Dermatology Research, Peninsula Medical School, Knowledge SpaRoyal Cornwall HospitalTruroUK

Personalised recommendations