5-Aminolevulinic Acid, but not 5-Aminolevulinic Acid Esters, is Transported into Adenocarcinoma Cells by System BETA Transporters

Topical or systemic administration of 5-aminolevulinic acid (5-ALA)†, as used in photodynamic therapy (PDT), results in accumulation of porphyrins, in particular, protoporphyrin IX (PpIX) (1,2). The initial step in the heme synthesis pathway is the 5-ALA synthase–induced formation of 5-ALA from succinyl-CoA and glycine, and this step is regulated by feedback inhibition by heme (3). By treating cells with 5-ALA, this negative feedback can be overruled. Due to the hydrophilic properties of ALA, ALA-PDT may clinically be limited by the rate of ALA uptake into the neoplastic cells and/or its penetration through the tissue (55,56). Clinical work has shown that more than 90% of superficial basal cell carcinomas (BCC) respond well to the topically applied ALA-based PDT. But, there is a low complete response rate to this treatment for the nodular BCC which comprises 45– 60% of all the BCC. 5-ALA esters with increased lipophilicity have therefore been established in order to increase the penetration depth of the precursor and efficacy of 5-ALA in PDT. Preclinical studies indicate that 5-ALA esters induce PpIX more efficiently after topic applications than 5-ALA (57) and phase-III clinical trials with 5-ALA methyl ester for BCC have been initiated. The initial step in the 5-ALA–induced synthesis of porphyrins is the penetration of 5-ALA through the plasma membrane. This step may be a rate-limiting factor in the formation of PpIX. This is also in accordance with the observation that esterification of 5-ALA with aliphatic alcohols (C6 or longer) was found to reduce 30–150-fold the amount of drug needed to reach the same level of PpIX accumulation (4). Such observations indicate that long-chain 5-ALA esters are taken up more efficiently and through other pathways than 5-ALA. However, the mechanisms associated with the uptake of 5-ALA and 5-ALA esters in neoplastic cells are not known. This prompted us to study the plasma membrane transport of 5-ALA in a human adenocarcinoma cell line (WiDr). It is shown in this report that 5-ALA, but not 5-ALA esters, is taken up by carrier systems transporting the b-amino acids, b-alanine and taurine, as well as g-aminobutyric acid (GABA) in these cells. Adjunto: 5ala-but-not-5mal-is-transported-by-system-beta-transp.pdf