Photodynamic therapy: regulation of porphyrin synthesis and hydrolysis from ALA esters.
Photodynamic therapy (PDT) is a tool for the treatment of certain cancerous and pre-cancerous conditions. The natural precursor of porphyrins 5-aminolevulinic acid (ALA) has been extensively used as a pro-photosensitiser in PDT. ALA's poor permeability has been enhanced by chemical esterification with aliphatic alcohols. Some of the ALA esters proved to be more efficient than ALA for porphyrin synthesis. In the present work we studied the nature of porphyrin synthesis regulation from the ALA esters Hexyl-ALA (He-ALA) and R,S-ALA-2-(hydroxymethyl)tetrahydropyranyl ester (THP-ALA) in an adenocarcinoma cell line. We found that He-ALA is incorporated into the cells at a higher rate, followed by THP-ALA and ALA, whereas ALA and ALA esters efflux at the same rate mediated by passive diffusion. Although ALA entrance to the cell might be regulatory at low concentrations, ALA derivative uptake is not a limiting factor. At high concentrations, the regulation of ALA conversion into porphyrins is driven by the enzyme porphobilinogenase, whereas ALA esters hydrolysis is regulated by esterases. The key conclusion of this contribution is that the use of ALA esters has to be limited to low concentrations where no regulation on porphyrin synthesis takes place.
Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), CONICET and Hospital de Clínicas José de San Martín, University of Buenos Aires, Córdoba 2351 1er subsuelo, Ciudad de Buenos Aires, CP 1120AAF, Argentina.
Gabriela
G
Di Venosa
Haydée
H
Fukuda
Alcira
A
Batlle
Alexander
A
Macrobert
Adriana
A
Casas
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism; D000622:Aminolevulinic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active; D045744:Cell Line, Tumor; D005260:Female; D006868:Hydrolysis; D007700:Kinetics; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D010778:Photochemotherapy; D011166:Porphyrins / Q000096:biosynthesis* / Q000378:metabolism
D011166:Porphyrins; D000622:Aminolevulinic Acid