Porphyrin synthesis, regulation and hydrolysis from ALA esters in Photodynamic Therapy

DI VENOSA G, FUKUDA H, CASAS A, BATLLE A

Hull, Inglaterra

Workshop; Tetrapyrrole Discussion Group; 2005

Tetrapyrrole Discussion Group

Photodynamic treatment (PDT) is a tool for the treatment of certain cancerous and pre-cancerous conditions, involving the presence of a photosensitiser and light. The natural precursor of porphyrins 5-aminolevulinic acid (ALA) has been extensively used as a pro-photosensitiser in PDT and in the detection of superficial malignancies. Because ALA is a polar compound, its inherently poor permeability was enhanced by chemical esterification with aliphatic alcohols.  Some of the ALA esters proved to be more efficient than ALA in terms of porphyrin synthesis when employed at low concentrations. 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-(hydroximethyl) tetrahydropyranyl ester (THP-ALA) in an adenocarcinoma cell line.  We found that He-ALA is incorporated into the cells at a higher rate and more quickly, followed by THP-ALA and ALA. Whereas on the other hand, both ALA and ALA esters efflux from the cells at the same rate mediated by passive diffusion.  Although ALA entrance to the cell might be regulating porphyrin raise, ALA derivatives uptake appears not to be a limiting factor. The regulation of ALA conversion into porphyrins is driven by the enzyme porphobilinogenase, whereas ALA esters hyrdrolisis is regulated by esterases.  As long as no ALA is consumed, no hydrolisis will take place and porphyrin outcome is not necessary for this regulation. This important contribution indicates that the use of ALA esters has to be limited to low concentrations where no regulation is excerpted.