Abstract
Exogenous administration of 5-aminolaevulinic acid (ALA) is becoming widely used to enhance the endogenous synthesis of protoporphyrin IX (PpIX) in photodynamic therapy (PDT) and fluorescence photodetection (PD). Recently, results have shown that the chemical modification of ALA into its more lipophilic esters circumvents limitations of ALA-induced PpIX like shallow penetration depth into deep tissue layers and inhomogeneous biodistribution and enhances the total PpIX formation. The present clinical pilot study assesses the feasibility and the advantages of a topical ALA ester-based fluorescence photodetection in the human bladder. In this preliminary study 5-aminolaevulinic acid hexylester (h-ALA) solutions, containing concentrations ranging from 4 to 16 mM, were applied intravesically to 25 patients. Effects of time and drug dose on the resulting PpIX fluorescence level were determined in vivo with an optical fibre-based spectrofluorometer. Neither local nor systemic side-effects were observed for the applied conditions. All conditions used yielded a preferential PpIX accumulation in the neoplastic tissue. Our clinical investigations indicate that with h-ALA a twofold increase of PpIX fluorescence intensity can be observed using 20-fold lower concentrations as compared to ALA.
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References
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: 688–697.
Bezdetnaya, L., Zeghari, N., Belitchenko, I., Berberi-Heyob, M., Merlin, J. L., Potapenko, A. & Guillemin, F. (1996) Spectroscopic and biological testing of photobleaching of porphyrins in solutions. Photochem Photobiol 64: 382–386.
Bridges, J. W., Sargent, N. S. E. & Upshall, D. G. (1979) Rapid absorption from the urinary bladder of a series of n-alkyl carbamate: a route for the recirculation of drug. Br J Pharmacol 66: 283–289.
Chang, S. G., MacRobert, A. J. & Bown, S. G. (1996) Biodistribution of protoporphyrin IX in rat urinary bladder after intravesical instillation of 5-aminolaevulinic acid. J Urol 155: 1744–1748.
Chang, S. G., MacRobert, A. J., Porter, J. B. & Bown, S. G. (1997) The efficacy of an iron chelator (CP94) in increasing cellular protoporphyrin IX following 5-aminolaevulinic acid administration: an in vivo study. J Photochem Photobiol B 38: 114–122.
Cox, G. S., Bobillier, C. & Whitten, D. G. (1982). Photo-oxidation and singlet oxygen sensitization by protoporphyrin IX and its photo-oxidation products. Photochem Photobiol 36: 401–407
Dougherty, T. J., Cooper, M. T. & Mang, T. S. (1990) Cutaneous phototoxic occurrences in patients receiving Photofrin. Lasers Surg Med 10: 485–488.
Fraga, C. G., Onuki, J., Lucesoli, F., Bechara, E. J. & Di Mascio, P. (1994) 5-Aminolaevulinic acid mediates the in vivo and in vitro formation of 8-hydroxy-2’-deoxyguanosine in DNA. Carcinogenesis 15: 2241–2244.
Fukuda, H., Paredes, S. & Del Battle, A. M. (1992) Tumor localizing properties of porphyrins in vivo studies using free and liposome encapsulated aminolaevulinic acid. Comp Biochem Physiol 102b: 433–436.
Gaullier, J. M., Berg, K., Peng, Q., Anholt, H., Selbo, P. K., Ma, L. W. & Moan, J. (1997) Use of 5-aminolaevulinic acid esters to improve photodynamic therapy on cells in culture. Cancer Res 57: 1481–1486.
Hanania, J. & Malik, Z. (1992) The effect of EDTA and serum on endogenous porphyrin accumulation and photodynamic sensitization of human leukemic cells. Cancer Lett 65: 127–131.
Hermanek, P. & Sobin, J. (1992). UICC TNM Classification of Malignant Tumours, 4th edn. Springer Verlag: Berlin
Hermes-Lima, M. (1995) How do Ca2+ and 5-aminolaevulinic acid-derived oxyradicals promote injury to isolated mitochondria?. Free Radical Biol Med 19: 381–390.
Iinuma, S., Bachor, R., Flotte, T. & Hasan, T. (1995) Biodistribution and phototoxicity of 5-aminolaevulinic acid-induced PpIX in an orthotopic rat bladder tumor model. J Urol 153: 802–806.
Jain, R. K. (1987a) Transport of molecules in the tumor interstitium: a review. Cancer Res 47: 3039–3305.
Jain, R. K. (1987b) Transport of molecules across tumor vasculature. Cancer Metast Rev 6: 559–593.
Jichlinski, P., Forrer, M., Mizeret, J., Glanzmann, T., Braichotte, D., Wagniéres, G., Zimmer, G., Guillou, L., Schmidlin, F. M., Graber, P., van den Bergh, H. & Leisinger, H. J. (1997) Clinical evaluation of a method for detecting superficial transitional cell carcinoma of the bladder by light-induced fluorescence of protoporphyrin IX following topical application of 5-aminolaevulinic acid: preliminary results. Lasers Surg Med 20: 402–408.
Kennedy, J. C., Pottier, R. H. & Pross, D. C. (1990) Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience. J Photochem Photobiol. B 6: 143–148.
Kloek, J. & Beijersbergen van Henegouwen, G. M. J. (1996) Prodrugs of 5-aminolaevulinic acid for photodynamic therapy. Photochem Photobiol 64: 994–1000.
Kriegmair, A., Baumgartner, R., Knuechel, R., Steinbach, P., Ehsan, A., Lumper, W., Hofstaeder, W. & Hofstetter, A. (1994) Fluorescence photodetection of neoplastic urothelial lesions following intravesical instillation of 5-aminolaevulinic acid. Urology 44: 836–841.
Kriegmair, M., Baumgartner, R., Lumper, W., Waidelich, R. & Hofstetter, A. (1996) Early clinical experience with 5-aminolaevulinic acid for the photodynamic therapy of superficial cancer. Br J Urol 77: 667–671.
Leveckis, J., Burn, J. L., Brown, N. J. & Reed, M. W. R. (1994) Kinetics of endogeneous protoporphyrin IX induction by aminolaevulinic acid: preliminary studies in the bladder. J Urol 152: 550–553.
Levi, F. (1993) Incidence of infiltrating cancer following superficial bladder carcinoma. Int J Cancer 55: 419–421.
Loh, C. S., Vernon, D., MacRobert, A. J., Bedwell, J., Bown, S. G. & Brown, S. B. (1993). Endogenous porphyrin distribution induced by 5-aminolevulinic acid in tissue layers of the gastrointestinal tract. Photochem Photobiol 20: 47–54
Marti, A., Lange, N., van den Bergh, H., Sedmera, D., Jichlinski, P. & Kuchera, P. (1998). Optimalisation of the formation and distribution of protoporphyrin IX in the urothelium: an in vitro approach. J Urol (in press)
Moan, J., Streckyte, G., Bagdonas, S., Bech, O. & Berg, K. (1997). Photobleaching of protoporphyrin IX in cells incubated with 5-aminolevulinic acid. Int J Cancer 70: 90–97
Mostofio, F. K., Sobin, L. H. & Torloni, H. (1973). Histological typing of urinary bladder tumors. In International Histological Classification of Tumors. World Health Organization Geneva
Nagy, G. K., Frable, W. J. & Murphy, W. M. (1982). Classification of premalignant urothelial abnormalities: A Delphi study of the National Bladder Cancer Collaborative Group A. In Sommers SC and Rosen PP (eds) pp. 219–233 Appleton: Norwalk, CT
Novo, M., Huettmann, G. & Diddens, H. (1996) Chemical instability of 5-aminolaevulinic acid used in the fluorescence diagnosis of bladder tumours. J Photochem Photobiol B 34: 143–148.
Orenstein, A., Kostenich, G., Tsur, H., Roitman, L., Ehrenberg, B. & Malik, Z. (1995) Photodynamic therapy of human skin tumors using topical application of 5-aminolaevulinic acid, DMSO and EDTA. Proc SPIE 2325: 100–105.
Ortel, B., Tanew, A. & Honigsmann, H. (1993) Lethal photosensitization by endogenous porphyrins of PAM cell-modification by desferrioxamine. J Photochem Photobiol B 17: 273–278.
Peng, Q., Moan, J., Warlow, T., Nesland, J. M. & Rimington, C. (1992) Distribution and photosensitizing efficiency of porphyrins induced by application of endogenous 5-aminolaevulinic acid in mice bearing mammary carcinoma. Int J Cancer 52: 433–443.
Peng, Q., Warloe, T., Moan, J., Heyerdahl, H., Steen, H. B., Nesland, J. M. & Giercksky, K. E. (1995) Distribution of 5-aminolaevulinic acid-induced porphyrins in noduloulcerative basal cell carcinoma. Photochem Photobiol 62: 906–913.
Peng, Q., Moan, J., Warloe, T., Irani, V., Steen, H. B., Bjorseth, A. & Nesland, J. M. (1996) Build-up of esterified aminolaevulinic-acid-derivative-induced porphyrin fluorescence in normal mouse skin. J Photochem Photobiol B 34: 96–96.
Rebeiz, N., Arkins, S., Rebebeiz, C. A., Simon, J., Zachary, J. F. & Kelly, K. W. (1996) Induction of tumour necrosis by δ-aminolaevulinic acid and 1,10-phenanthroline photodynamic therapy. Cancer Res 56: 339–344.
Richie, J. P., Shipley, W. U. & Yagoda, A. (1989). Cancer of the bladder. In Cancer Principles and Practice of Oncology, De Vita VT, Hellmann S and Rosenberg SA (eds), pp. 1008–1020. JB Lippincott: Philadelphia
Rick, K., Sroka, R., Stepp, H., Kriegmair, M., Huber, R. M. & Baumgartner, R. (1997) Pharmacokinetics of 5-aminolaevulinic acid-induced protoporphyrin IX in skin and blood. J Photochem Photobiol B 40: 319–313.
Rotomski, R., Bagdonas, S. & Streckyte, G. (1996) Spectroscopic studies of photobleaching and photoproduct formation of porphyrins used in tumour therapy. J Photochem Photobiol B 33: 61–67.
Schoenfeld, N., Mamet, R., Norenberg, Y., Shafran, M., Babuskin, T. & Malik, Z. (1994) Protoporphyrin biosynthesis in melanoma B 16 cells stimulated by 5-aminolaevulinic acid and chemical inducers: characterization of photodynamic inactivation. Int J Cancer 56: 106–112.
Steinbach, P., Kriegmair, M., Baumgartner, R., Hofstadter, F. & Knuechel, R. (1994) Intravesical instillation of 5-aminolaevulinic acid: the fluorescent metabolite is limited to urothelial cells. Urology 44: 676–681.
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 tumors of the skin using topical d-aminolaevulinic acid sensitization and laser irradiation. Br J Dermatol 130: 743–751.
Takeya, H. (1992) Preparation of 5-aminolaevulinic acid alkyl esters as herbicides. Chem Abstr 116: P189633
Tyrrell, R. M., Pourzand, C. & van den Bergh, H. (1993). Unpublished results
Wagnière, S., Hadjur, C., Grosjean, P., Braichotte, D., Savary, J. F., Monnier, P. & van den Bergh, H. (1998). Clinical evaluation of cutaneous phototoxicity of 5, 10, 15, 20-tetra (m-hydroxyphenyl) chlorin. Photochem Photobiol 68: 382–387
Warloe, T., Peng, Q., Steen, H. B. & Gierchsky, K. E. (1992). Localization of porphyrins in human basal cell carcinoma and normal tissue induced by topical application of 5-aminolaevulinic acid. In Photodynamic Therapy and Biomedical Lasers, Spinelli P, Dal Fante M and Marchesini R (eds), pp. 454–458. Elvesier Science: Amsterdam
Warloe, T., Peng, Q., Heyerdahl, H., Moan, J., Stenn, H. B. & Giercksky, K. E. (1995) Photodynamic therapy with 5-aminolaevulinic acid induced porphyrins and DMSO/EDTA for basal cell carcinoma. Proc SPIE 2371: 226–235.
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Lange, N., Jichlinski, P., Zellweger, M. et al. Photodetection of early human bladder cancer based on the fluorescence of 5-aminolaevulinic acid hexylester-induced protoporphyrin IX: a pilot study. Br J Cancer 80, 185–193 (1999). https://doi.org/10.1038/sj.bjc.6690338
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DOI: https://doi.org/10.1038/sj.bjc.6690338