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The aim of this work was to test in vitro and in vivo the efficacy of the derivatives of 5-aminolevulinic acid (ALA): hexyl-ALA (He-ALA), undecanoyl-ALA and R,S-2-(hydroximethyl)tetrahydropyranyl-ALA (THP-ALA) as pro-photosensitising agents. The compounds were assayed in a cell line derived from a murine mammary tumour, in tumour explants and after injection of the cells into mice. In vitro, undecanoyl-ALA and THP-ALA did not improve ALA efficacy in terms of porphyrin synthesis. On the other hand, half of the amount of ALA is required to obtain the same plateau amount of photosensitiser from He-ALA. However, this plateau value cannot be surpassed in spite of the four-times higher accumulation of ALA/He-ALA from the ALA derivative. This shows that He-ALA conversion to porphyrins but not He-ALA entry to the cells is limiting. Employing ionic exchange chromatography, we found that 80% of total uptake was He-ALA whereas only 20% was ALA. This suggests that the esterases, probably themselves regulated by the heme pathway, are limiting the conversion of ALA derivatives into porphyrins. A similar situation occurs with THP-ALA. Tumour explant porphyrin results correlate well with cell line data. However, i.p. injection of ALA derivatives to mice resulted in a lower porphyrin concentration in the tumour when compared to the administration of equimolar amounts of ALA, indicating that there should be retention of ALA derivatives either within the blood vessels in the initial phase of distribution and/or within the capillaries of the tumour. © 2004 Cancer Research UK.


Documento: Artículo
Título:Porphyrin synthesis from ALA derivatives for photodynamic therapy. In vitro and in vivo studies
Autor:Perotti, C.; Fukuda, H.; DiVenosa, G.; MacRobert, A.J.; Batlle, A.; Casas, A.
Filiación:Ctro. Invest. Porfirinas P., Ciudad Universitaria, Pabellón II, (1428) Capital Federal, Argentina
National Medical Laser Centre, Roy. Free and Univ. Coll. Med. Sch., London, United Kingdom
Viamonte 1881 10A, Buenos Aires 1056, Argentina
Palabras clave:ALA; ALA derivatives; Aminolevulinic acid; PDT; Photodynamic therapy; 2 (hydroxymethyl)tetrahydropyranyl 5 aminolevulinic acid; aminolevulinic acid; hexyl 5 aminolevulinic acid; photosensitizing agent; porphyrin; unclassified drug; undecanoyl 5 aminolevulinic acid; aminolevulinic acid; drug derivative; photosensitizing agent; porphyrin; animal cell; animal experiment; animal model; animal tissue; article; bioaccumulation; breast tumor; cell line; controlled study; correlation analysis; drug determination; drug efficacy; drug uptake; explant; ion exchange chromatography; male; mouse; nonhuman; photodynamic therapy; phototoxicity; porphyrin metabolism; priority journal; animal; Bagg albino mouse; biosynthesis; chemistry; experimental neoplasm; methodology; photochemotherapy; Aminolevulinic Acid; Animals; Male; Mammary Neoplasms, Animal; Mice; Mice, Inbred BALB C; Photochemotherapy; Photosensitizing Agents; Porphyrins
Página de inicio:1660
Página de fin:1665
Título revista:British Journal of Cancer
Título revista abreviado:Br. J. Cancer
CAS:aminolevulinic acid, 106-60-5; porphyrin, 24869-67-8; Aminolevulinic Acid, 106-60-5; Photosensitizing Agents; Porphyrins


  • Batlle, A., (1997) Porfirias y Porfirinas. Aspectos Clínicos, Bioquímicos y Biología Molecular, , Buenos Aires, Argentina: ED: Acta Bioquímica Clinica Latinoamericana
  • Baumgartner, R., Huber, R., Schulz, H., Stepp, H., Rick, K., Gamarra, F., Leberig, A., Roth, C., Inhalation of 5-aminolevulinic acid: A new technique for fluorescence detection of early stage lung cancer (1996) J Photochem Photobiol B, 36, pp. 167-174
  • Bermúdez Moretti, M., Correa García, S., Perotti, C., Batlle, A., Casas, A., 5-Aminolevulinic acid transport in murine mammary adenocarcinoma cells is mediated by beta transporters (2002) Br J Cancer, 87, pp. 471-474
  • Casas, A., Batlle, A., Rational design of 5-aminolevulinic acid derivatives aimed at improving photodynamic therapy (2002) Curr Med Chem Anti-Cancer Agents, 2, pp. 465-475
  • Casas, A., Fukuda, H., Di Venosa, G., Batlle, A., Photosensitisation and mechanism of cytotoxicity induced by the use of ALA derivatives in photodynamic therapy (2001) Br J Cancer, 85, pp. 279-284
  • Casas, A., Perotti, C., Fukuda, H., Rogers, L., Butler, A., Batlle, A., ALA and ALA hexyl ester-induced porphyrin synthesis in chemically induced skin tumours: The role of different vehicles on improving photosensitisation (2001) Br J Cancer, 85, pp. 1740-1800
  • Denizot, F., Lang, R., Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability (1986) J Immunol Methods, 89, pp. 271-277
  • Di Venosa, G., Fukuda, H., Perotti, C., Batlle, A., Casas, A., A simple method for separating ALA from ALA derivatives using ionic exchange chromatography (2003) J Photochem Photobiol B, , submitted
  • Eléouet, S., Rousset, N., Carré, J., Bourré, L., Vonarx, V., Lajat, Y., Beijersbergen Van Henegouwen, G., Patrice, T., In vitro fluorescence, toxicity and phototoxicity induced by 5-aminolevulinic acid (ALA) or ALA-esters (2000) Photochem Photobiol, 71, pp. 447-454
  • Fukuda, H., Paredes, S., Batlle, A., Tumour-localizing properties of porphyrins. In vitro studies using the porphyrin precursor, aminolevulinic acid, in free and liposome encapsulated forms (1989) Drug Des Deliv, 6, pp. 133-139
  • Fukuda, H., Paredes, S., Batlle, A., Tumour-localizing properties of porphyrins. In vivo studies using free and liposome encapsulated aminolevulinic acid (1992) Comp Biochem Physiol, 102 B, pp. 433-436
  • Hilf, R., Smail, D., Murant, R., Leakey, P., Gibson, S., Hematoporphyrin derivative induced photosensitivity of mitochondrial succinate dehydrogenase and selected cytosolic enzymes of R3230AC mammary adenocarcinomas of rats (1984) Cancer Res, 44, pp. 1483-1488
  • Kennedy, J., Pottier, R., Pross, G., Photodynamic therapy with endogenous protoporphyrin IX: Basic principles and present clinical experience (1990) J Photochem Photobiol B, 6, pp. 143-148
  • Kloek, J., Akkermans, W., Beijersbergen Van Henegouwen, G., Derivatives of 5-aminolevulinic acid for photodynamic therapy: Enzymatic conversion into protoporphyrin (1998) Photochem Photobiol, 67, pp. 150-154
  • Krieg, R., Uihlein, D., Murthum, T., Endlicher, E., Hausmann, F., Messmann, H., Knuechel, R., Improving the use of 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PPIX) for the gastrointestinal tract by esterification - An in vitro study (2002) Cell Mol Biol, 48, pp. 917-923
  • Mauzerall, M., Granick, S., The occurrence and determination of 5-aminolevulinic acid and porphobilinogen in urine (1956) J Biol Chem, 219, pp. 435-437
  • Peng, Q., Warloe, T., Moan, J., Heyerdahl, H., Steen, H., Giercksky, K., Nesland, J., ALA derivative-induced protoporphyrin IX build-up and distribution in human nodular basal cell carcinoma (1995) Photochem Photobiol, 61, pp. 82S
  • Perotti, C., Casas, A., Fukuda, H., Sacca, P., Batlle, A., ALA and ALA hexyl ester induction of porphyrins after their systemic administration to tumour bearing mice (2002) Br J Cancer, 87, pp. 790-795
  • Polo, C.F., Navone, N.M., Afonso, S.G., Vazquez, E.S., Buzaleh, A.M., Bianchi, A., Schoua, E., Batlle, A., Induction of porphyrin biosynthesis in tissue explants and the effect of antimitotics (1988) ATLA, 16, pp. 137-147
  • Takeya, H., Preparation of 5-aminolevulinic acid alkyl esters as herbicides (1992) Chem Abstr, 116, pp. 189633m
  • Werbajh, S.E., Urtreger, A.J., Puricelli, L.I., De Lustig, E.S., Bal De Kier Joffe, E., Kornblihtt, A.R., Downregulation of fibronectin transcription in highly metastatic adenocarcinoma cells (1998) FEBS Lett, 440, pp. 277-281
  • Whitaker, C., Battah, S., Forsyth, M., Edwards, C., Boyle, R., Matthews, K., Photosensitization of pancreatic tumour cells by 5-aminolevulinic acid esters (2000) Anti-Cancer Drugs Des, 15, pp. 161-170
  • Workman, P., Twentyman, P., Balkwill, F., Balmain, A., Chaplin, D., Double, J., Embleton, J., Wallace, J., United Kingdom Co-ordinating Committee on Cancer Research (UKCCCR) Guidelines for the welfare of animals in experimental neoplasia (1998) Br J Cancer, 77, pp. 1-10. , Second Edition


---------- APA ----------
Perotti, C., Fukuda, H., DiVenosa, G., MacRobert, A.J., Batlle, A. & Casas, A. (2004) . Porphyrin synthesis from ALA derivatives for photodynamic therapy. In vitro and in vivo studies. British Journal of Cancer, 90(8), 1660-1665.
---------- CHICAGO ----------
Perotti, C., Fukuda, H., DiVenosa, G., MacRobert, A.J., Batlle, A., Casas, A. "Porphyrin synthesis from ALA derivatives for photodynamic therapy. In vitro and in vivo studies" . British Journal of Cancer 90, no. 8 (2004) : 1660-1665.
---------- MLA ----------
Perotti, C., Fukuda, H., DiVenosa, G., MacRobert, A.J., Batlle, A., Casas, A. "Porphyrin synthesis from ALA derivatives for photodynamic therapy. In vitro and in vivo studies" . British Journal of Cancer, vol. 90, no. 8, 2004, pp. 1660-1665.
---------- VANCOUVER ----------
Perotti, C., Fukuda, H., DiVenosa, G., MacRobert, A.J., Batlle, A., Casas, A. Porphyrin synthesis from ALA derivatives for photodynamic therapy. In vitro and in vivo studies. Br. J. Cancer. 2004;90(8):1660-1665.