5-Aminolevulinic acid and its derivatives: physical chemical properties and protoporphyrin IX formation in cultured cells

Uehlinger, Pascal; Zellweger, Matthieu; Wagnières, Georges; Juillerat‐Jeanneret, Lucienne; Bergh, Hubert van den; Lange, Norbert

doi:10.1016/s1011-1344(99)00159-1

Cited by 199 publications

(189 citation statements)

References 37 publications

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“…The optimum concentration of each ALA-ester was related to the length of the ester-linked chain, with longer-chain compounds inducing maximum porphyrin levels at lower concentrations than the shorter-chain derivatives. These findings are in broad agreement with previous observations (Gaullier et al, 1997;Kloek et al, 1998;Uehlinger et al, 2000).…”

Section: Discussionsupporting

confidence: 94%

“…This suggests that at least some murine tissues have Experimental Therapeutics the capacity to utilise certain ALA-esters for porphyrin synthesis, and that the results obtained in tumour tissue are not a reflection of murine metabolism per se. Previous work in vitro has suggested that a number of ALAesters, including hexyl-ALA, are most effective when used at much lower doses than ALA (Kloek et al, 1998;Lange et al, 1999;Uehlinger et al, 2000). Here, we found that reducing the dose of i.v.…”

Section: Discussionmentioning

confidence: 47%

“…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). A number of in vivo studies have suggested that topical application of some ALA esters can result in greater PpIX accumulation than similar concentrations of ALA (Peng et al, 1996;Lange et al, 1999;van den Akker et al, 2000).…”

mentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 47%

mentioning

confidence: 99%

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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 progression from an initially non-uniform PpIX distribution to one that is quite uniform and back again is illustrated in Figure 1 (D-F), where images are presented of spheroids incubated with 0.005 mM, 0.05 mM and 1 mM h-ALA. Figure 3 displays the average fluorescence in the optical sections for the entire range of incubation concentrations for ALA and h-ALA. Both plots share a qualitatively similar increase and subsequent decrease in fluorescence with pro-drug concentration that agrees well with results obtained from other cell lines in monolayer cell culture (Uehlinger et al, 2000). The maximum value of the total PpIX fluorescence signal for h-ALA is nearly equal to that observed for ALA.…”

Section: Ala-and H-ala-induced Ppix Fluorescence In Spheroids 729supporting

confidence: 87%

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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“…The latter's density is quantified by its absorption of visible light (570 nm). MTT (1 mg ml À1 ) was added to each well (100 ml) and cells incubated for 3 h, 371C, 5% CO 2 (Uehlinger et al, 2000). MTT was replaced with dimethyl sulphoxide (100 ml/well) to dissolve formazan crystals.…”

Section: Mtt Assaymentioning

confidence: 99%

Photochemical internalisation of chemotherapy potentiates killing of multidrug-resistant breast and bladder cancer cells

et al. 2007

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Multidrug resistance (MDR) is the major confounding factor in adjuvant solid tumour chemotherapy. Increasing intracellular amounts of chemotherapeutics to circumvent MDR may be achieved by a novel delivery method, photochemical internalisation (PCI). PCI consists of the co-administration of drug and photosensitiser; upon light activation the latter induces intracellular release of organellebound drug. We investigated whether co-administration of hypericin (photosensitiser) with mitoxantrone (MTZ, chemotherapeutic) plus illumination potentiates cytotoxicity in MDR cancer cells. We mapped the extent of intracellular co-localisation of drug/ photosensitiser. We determined whether PCI altered drug-excreting efflux pump P-glycoprotein (Pgp) expression or function in MDR cells. Bladder and breast cancer cells and their Pgp-overexpressing MDR subclones (MGHU1, MGHU1/R, MCF-7, MCF-7/R) were given hypericin/MTZ combinations, with/without blue-light illumination. Pilot experiments determined appropriate sublethal doses for each. Viability was determined by the 3-[4,5-dimethylthiazolyl]-2,5-diphenyltetrazolium bromide assay. Intracellular localisation was mapped by confocal microscopy. Pgp expression was detected by immunofluorescence and Pgp function investigated by Rhodamine123 efflux on confocal microscopy. MTZ alone (0.1 -0.2 mg ml À1 ) killed up to 89% of drug-sensitive cells; MDR cells exhibited less cytotoxicity (6 -28%). Hypericin (0.1 -0.2 mM) effects were similar for all cells; light illumination caused none or minimal toxicity. In combination, MTZ /hypericin plus illumination, potentiated MDR cell killing, vs hypericin or MTZ alone. (MGHU1/R: 38.65 and 36.63% increase, Po0.05; MCF-7/R: 80.2 and 46.1% increase, Po0.001). Illumination of combined MTZ/hypericin increased killing by 28.15% (Po0.05 MGHU1/R) compared to dark controls. Intracytoplasmic vesicular co-localisation of MTZ/hypericin was evident before illumination and at serial times post-illumination. MTZ was always found in sensitive cell nuclei, but not in dark resistant cell nuclei. In illuminated resistant cells there was some mobilisation of MTZ into the nucleus. Pgp expression remained unchanged, regardless of drug exposure. Pgp efflux was blocked by the Pgp inhibitor verapamil (positive control) but not impeded by hypericin. The increased killing of MDR cancer cells demonstrated is consistent with PCI. PCI is a promising technique for enhancing treatment efficacy.

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5-Aminolevulinic acid and its derivatives: physical chemical properties and protoporphyrin IX formation in cultured cells

Cited by 199 publications

References 37 publications

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

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

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

Photochemical internalisation of chemotherapy potentiates killing of multidrug-resistant breast and bladder cancer cells

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