Alcira Batlle

The use of endogenous protoporphyrin IX generated after administration of 5-aminolaevulinic acid (ALA) has led to many applications in photodynamic therapy (PDT). However, the bioavailability of ALA is limited by its hydrophilic properties and limited cell uptake. A promising approach to optimize the efficacy of ALA-PDT is to deliver ALA in the form of prodrugs to mask its hydrophilic nature. The aim of this work was to evaluate the potential of two ALA dipeptide derivatives, N-acetyl terminated leucinyl-ALA methyl ester (Ac-Leu-ALA-Me) and phenylalanyl-ALA methyl ester (Ac-Phe-ALA-Me), for their use in PDT of cancer, by investigating the generation of protoporphyrin IX in an oncogenic cell line (PAM212-Ras), and in a subcutaneous tumor model. In our in vitro studies, both derivatives were more effective than ALA in PDT treatment, at inducing the same protoporphyrin IX levels but at 50- to 100-fold lower concentrations, with the phenylalanyl derivative being the most effective. The efficient release of ALA from Ac-Phe-ALA-Me appears to be consistent with the reported substrate and inhibitor preferences of acylpeptide hydrolase. In vivo studies revealed that topical application of the peptide prodrug Ac-Phe-ALA-Me gave greater selectivity than with ALA itself, and induced tumor photodamage, whereas systemic administration improved ALA-induced porphyrin generation in terms of equivalent doses administered, without induction of toxic effects. Our data support the possibility of using particularly Ac-Phe-ALA-Me both for topical treatment of basal cell carcinomas and for systemic administration. Further chemical fine-tuning of this prodrug template should yield additional compounds for enhanced ALA-PDT with potential for translation to the clinic.

Protoporphyrin IX

10.1158/1535-7163.mct-13-1084

Cite

Citations (14)

The porphobilinogen deamise ‐ uroporphyrinogen III cosynthetase system (porphobilinogenase) from bovine liver. Kinetic studies

FEBS Letters (1969)

Horacio A. Sancovich Alcira Batlle M. Grinstein

10.1016/0014-5793(69)80142-0

Cite

Citations (15)

Folding and unfolding of δ-aminolevulinic acid dehydratase and porphobilinogen deaminase induced by uro- and protoporphyrin

The International Journal of Biochemistry & Cell Biology (1997)

Susana G. Afonso Rafael Enrı́quez de Salamanca Alcira Batlle

Porphobilinogen deaminase

Porphobilinogen

Proteolysis

Protoporphyrin IX

Denaturation (fissile materials)

10.1016/s1357-2725(96)00093-3

Cite

Citations (9)

Porphyrin Biosynthesis Intermediates Are Not Regulating δ-Aminolevulinic Acid Transport in Saccharomyces cerevisiae

Biochemical and Biophysical Research Communications (2000)

Mariana Bermúdez Moretti Susana Correa Garcı́a Alcira Batlle

Ferrochelatase

Uroporphyrinogen III decarboxylase

10.1006/bbrc.2000.2874

Cite

Citations (11)

Yeast Porphobilinogen Deaminase also Forms Enzyme-Pyrrole Intermediates

Enzyme and Protein (1994)

Susana Correa Garcı́a María Victoria Rossetti Mariana Bermúdez Moretti Alcira Batlle

The enzyme porphobilinogen deaminase (PBG deaminase. EC 4.3.1.8) catalyzes the condensation of four molecules of PBG to give the linear tetrapyrrol, hydroxymethylbilane. It has been shown that this enzyme forms stable mono-, di-, tri- and tetrapyrrol-enzyme covalent complexes. When the enzyme, partially purified in the absence or presence of phenylmethylsulfonyl fluoride (PMSF) and preincubated with PBG. was applied on DEAE-cellulose columns, three peaks with PBG deaminase activity were detected. Using Ehrlich's reagent, it was found that the active peaks corresponded to mono-, di- and tri-pyrrylmethane-enzyme complexes. Therefore, the mechanism of action of PBG deaminase from Saccharomyces cerevisiae also involves the sequential addition of four PBG units, leading to the formation of the enzyme-substrate intermediate complexes, as has already been described for the same enzyme from other sources.

Porphobilinogen deaminase

Phenylmethylsulfonyl Fluoride

Porphobilinogen

10.1159/000475000

Cite

Citations (3)

Papers

Citation

H-Index

i-10 index

Papers

Citation

H-Index

i-10 index