Porphyrin accumulation induced by 5-aminolaevulinic acid esters in tumour cells growing in vitro and in vivo

Abstract

The ability of 5-aminolaevulinic acid and some of its esterified derivatives to induce porphyrin accumulation has been examined in CaNT murine mammary carcinoma cells growing in culture and as tumours in vivo. Topical or intravenous administration of 5-aminolaevulinic acid-esters to mice bearing subcutaneous tumours produced lower porphyrin levels in the tumour than an equimolar dose of 5-aminolaevulinic acid. Reducing the dose of intravenous hexyl-or benzyl-ALA and topical hexyl-5-aminolaevulinic acid resulted in a dose-dependent reduction in porphyrin accumulation. A number of normal tissues accumulated higher concentrations of porphyrins than tumour tissue following intravenous administration of 5-aminolaevulinic acid-esters. Esterase activity in these normal tissues was greater than that in tumour tissue. In contrast to the situation in vivo, all of the 5-aminolaevulinic acid-esters examined were at least as effective as 5-aminolaevulinic acid when applied to cloned CaNT cells in vitro, with the drug concentration required for maximum porphyrin accumulation varying with ester chain-length. Tumour cells growing in culture released esterase activity into the medium. These findings suggest that the efficacy of 5-aminolaevulinic esters may vary depending on the esterase activity of the target tissue, and suggest caution when interpreting the findings of in vitro studies using these and similar prodrugs.

Oil components modulate the skin delivery of 5-aminolevulinic acid and its ester prodrug from oil-in-water and water-in-oil nanoemulsions

“…Some in vivo studies 39,40 suggested that topical application of ALA esters can result in greater PpIX accumulation than ALA. Although mALA exhibited a lower in vitro cumulative amount in the receptor compared to ALA, the in vivo CLSM results showed comparable fluorescence intensities between ALA and mALA.…”

A porphobilinogen deaminase (PBGD) Ran-binding protein interaction is implicated in nuclear trafficking of PBGD in differentiating glioma cells

“…An increased growth rate in both nonmalignant and malignant cell lines was strongly correlated with an increased activity of PBGD (Schoenfeld et al, 1988). PpIX biosynthesis and accumulation in a variety of malignant tissues following 5-ALA administration has been clinically exploited for photodynamic therapy and photodiagnosis (Stummer et al, 1998;Tunstall et al, 2002).…”

Estudo da pele humana fotoenvelhecida após tratamento com terapia fotodinâmica associada ao ácido 5-delta-aminolevulínico tópíco: avaliação imunoistoquímica, do colágeno e do tecido elástico

“…O ALA é uma molécula hidrofílica, pequena, com 167,6 daltons e que não penetra facilmente na pele íntegra, mas penetra na pele danificada, sendo maior nos tecidos queratinizados anormais; por isso é utilizado como precursor do PpIX, que é uma molécula grande 126,146,147,181,195,196,[201][202][203] .…”

“…O modo de aplicação do ALA pode ser sistêmico; oral ou intravenoso, tópico ou intratumoral, seguido por um período de exposição de 4 a 72 horas dependendo da farmacocinética do fotossensibilizante, permitindo seu acúmulo no tumor 203,205 . de Blois et al…”

“…Os derivados ésteres (metil, etil, propil, butil, pentil, hexil e octiltabela) do ALA são lipofílicos, pois apresentam um aumento no número de carbonos em sua cadeia, e passam a barreira cutânea mais facilmente 203,215,216 . Alterações da acuidade visual e polineuropatia motora associada a lesões cutâneas, mimetizando quadro de porfiria hepática, são complicações citadas na literatura 291,292 .…”