5‐Aminolevulinic Acid‐Based Photodynamic Therapy: Principles and Experimental Research

Peng, Qian; Berg, Kristian; Moan, Johan Emelian; Kongshaug, Magne; Nesland, Jahn M.

doi:10.1111/j.1751-1097.1997.tb08549.x

Cited by 591 publications

(526 citation statements)

References 198 publications

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“…This response to high concentrations of both pro-drugs is similar, therefore it must be caused by the ALA itself. Mechanisms of ALA dark toxicity have been reviewed by Peng et al (1997). In our experiments, the concentrations of ALA and h-ALA at which this overall reduction was evident were 15 and 2 mM, respectively.…”

Section: Discussionmentioning

confidence: 58%

ALA- and ALA-hexylester-induced protoporphyrin IX fluorescence and distribution in multicell tumour spheroids

Bigelow¹,

Mitra

Knuechel

et al. 2001

Br J Cancer

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Synthesis of protoporphyrin IX (PpIX) in intact murine mammary cancer cell spheroids is reported from optical sections obtained using a laser scanning confocal fluorescence microscope. EMT6 spheroids 275–350 μ m in diameter were incubated in 0.1–15 mM aminolevulinic acid (ALA) or 0.001–2 mM ALA-hexylester (h-ALA) to test the ability of both pro-drugs to diffuse into the spheroids and induce PpIX production. Spheroids incubated with ALA show significant fluorescence nonuniformity for all concentrations, with the outermost cells exhibiting greater porphyrin fluorescence. Comparable levels of fluorescence throughout the optical section are achieved with approximately 100-fold lower h-ALA concentrations, indicating that the interior cells maintain esterase activity and porphyrin synthesis and that h-ALA diffuses efficiently to the spheroid interior. Fluorescence gradients are less pronounced with h-ALA incubation, in part because of apparent saturation of esterase activity in the spheroid perimeter. Proliferating (Ki67 positive) and quiescent cell populations exhibit remarkably different h-ALA concentration dependencies. The incubation concentration resulting in maximum fluorescence with ALA is 10 mM, while the optimal concentration for h-ALA is 200-fold lower at 0.05 mM. Exceeding these optimal concentrations for both pro-drugs leads to an overall loss of fluorescence. © 2001 Cancer Research Campaign http://www.bjcancer.com

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Section: Discussionmentioning

confidence: 58%

ALA- and ALA-hexylester-induced protoporphyrin IX fluorescence and distribution in multicell tumour spheroids

Bigelow¹,

Mitra

Knuechel

et al. 2001

Br J Cancer

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“…Since ALA-S is the rate limiting step in PpIX synthesis, exogenous ALA is efficiently converted to PpIX. 5 ALA-S production is tightly regulated in the cell, presumably to avoid the toxic accumulation of PpIX and related porphyrins. There are two forms of ALA-S, an erythroid form and a constitutive or hepatic form.…”

Section: Introductionmentioning

confidence: 99%

A photosensitising adenovirus for photodynamic therapy

Gagnebin

Brunori²,

Otter³

et al. 1999

Gene Ther

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We have developed a new approach to photodynamic thervirus genome and used it to construct a virus expressing apy based on adenoviral transduction of the rate-limiting a mutant form of ALA-S lacking the iron response elements enzyme in heme synthesis. Conventional phototherapy which regulate ALA-S translation and the heme regulatory uses porphyrin-based chemical photosensitisers, including motifs which regulate import of ALA-S into mitochondria. ␦-aminolaevulinic acid (ALA) which is converted to protoThe virus induces a large increase in PpIX expression and porphyrin IX (PpIX) by the enzymes of the heme biosynconfers photosensitivity on cultured cells. Unlike conventhetic pathway. The lack of a specific mechanism for tartional photodynamic therapy, a viral approach makes it geting chemical photosensitisers and PpIX to tumour cells possible to restrict photosensitivity by biological rather than means that therapeutic irradiation can damage normal purely physical or chemical means. As with HSV thymidine tissue and exposure to sunlight following treatment can kinase, ALA-S expression is a general mechanism for cause severe burns. The rate limiting enzyme in PpIX sensitisation to a therapeutic agent which can easily be synthesis is ALA-synthase (ALA-S). We have developed a adapted to whatever means of gene delivery is most new yeast vector system for manipulation of the adenoeffective.

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“…The hydrophilic nature of ALA (Novo Rodriguez et al, 1995) may limit its ability to penetrate through skin or cell membranes (Peng et al, 1997a) and thereby restrict its topical use to the treatment of superficial disease. As a result, esterified derivatives of ALA, which are less hydrophilic than the parent compound (Uehlinger et al, 2000), are under investigation as possible alternatives to ALA. Work in vitro has demonstrated that a number of cell lines have the ability to take-up and metabolise certain ALA-esters into PpIX at a faster rate, and at lower concentrations, than ALA (Kloek and Beijersbergen van Henegouwen, 1996;Peng et al, 1996).…”

mentioning

confidence: 99%

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

et al. 2002

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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.

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5‐Aminolevulinic Acid‐Based Photodynamic Therapy: Principles and Experimental Research

Cited by 591 publications

References 198 publications

ALA- and ALA-hexylester-induced protoporphyrin IX fluorescence and distribution in multicell tumour spheroids

ALA- and ALA-hexylester-induced protoporphyrin IX fluorescence and distribution in multicell tumour spheroids

A photosensitising adenovirus for photodynamic therapy

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

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