Topical application of 5-aminolevulinic acid, DMSO and EDTA: protoporphyrin IX accumulation in skin and tumours of mice

Malik, Zvi; Kostenich, Genady; Roitman, Leonid; Ehrenberg, Benjamin; Orenstein, Arie

doi:10.1016/1011-1344(95)07117-k

Cited by 131 publications

(92 citation statements)

References 13 publications

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“…Malik et al (1995) observed an increase in fluorescence intensity of normal mouse skin up to 2-4 h after the end of 2 h topically applied ALA. It may be possible that during the 4 h application, on the skin of hairless mice, a large depot of ALA is formed in the horny layer or in other parts of the skin.…”

Section: Discussionmentioning

confidence: 84%

Kinetics and localisation of PpIX fluorescence after topical and systemic ALA application, observed in skin and skin tumours of UVB-treated mice

Veen¹,

Bruijn²,

Berg³

et al. 1996

Br J Cancer

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SummaryIn this study the kinetics and localisation of protoporphyrin IX (PpIX) fluorescence in skin and skin tumours were examined after topically (20% for 4 h) or systemically (200 mg kg-', i.p.) administered 5-aminolaevulinic acid (ALA). As a model we used hairless mice with skin lesions (actinic keratoses and squamous cell carcinoma), which were induced by daily UVB irradiation. The epidermis of the skin surrounding the tumours (T) was altered (AS); owing to the UVB irradiation, the epidermis was thicker and less elastic. Therefore, non-UVBirradiated mice were used to assess fluorescence of normal skin (NS). Light from a halogen lamp was used to excite at 500 + 20 nm and fluorescence was detected through a filter that passes light of 670 + 50 nm. Maximal fluorescence following i.p. ALA was observed 2 h post injection (p.i.) and was three times less than after topically applied ALA. Furthermore, after i.p. ALA a lower T selectively (T/NS) could be obtained than after topically applied ALA. Maximal fluorescence following topically applied ALA was achieved 6 h after the end of the 4 h application time. At that interval fluorescence of T was twice as high as directly after the application period. Furthermore, T selectivity (T/NS) after topical ALA at the interval of maximal fluorescence was higher than at the interval directly after application. With fluorescence cryomicroscopy localisation of fluorescence in the skin at the interval of maximal fluorescence was determined after both administration routes. For both cases fluorescence was mainly located in T, epidermis and hair follicles. Fluorescence in subcutis could only be observed at 2 h post i.p. ALA and at 6 h post topical ALA. No fluorescence could be observed in muscle. We conclude that, in this model and with these ALA doses, a higher fluorescence intensity and selectivity (T/NS) was achieved after topically applied ALA than after systemically administered ALA. These results make topically applied ALA more favourable for ALA-PDT of superficial skin tumours in this model. In general these results imply that by optimising the time after ALA application the efficacy and selectivity of topical ALA-PDT for skin tumours may be improved.

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Section: Discussionmentioning

confidence: 84%

Kinetics and localisation of PpIX fluorescence after topical and systemic ALA application, observed in skin and skin tumours of UVB-treated mice

Veen¹,

Bruijn²,

Berg³

et al. 1996

Br J Cancer

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“…LIF, which is based on a point measurement of signals from a fluorescence probe (fluorophore) following laser-induced activation of the tissue-sequestered compound, 20 was used for quantitative assessment of HY distributed in organs of tumor-free and tumor-bearing (TB) animals. BALB/c mice inoculated with primary DA3 or SQ2 tumors and bearing lung metastases (approximately 50 days post tumor inoculation), were injected with HY (10 mg/kg; i.p.).…”

Section: Hy Accumulation In Murine Organsmentioning

confidence: 99%

Antimetastatic activity of the photodynamic agent hypericin in the dark

Blank

Lavie²,

Mandel³

et al. 2004

Intl Journal of Cancer

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A unique property of the photodynamic signal transduction inhibitor hypericin (HY) is high functionality in the dark, which has been shown to result in portfolio of anticancer activities both in vitro and in vivo. Here we show that treatment with HY significantly reduces growth rate of metastases in 2 murine models: breast adenocarcinoma (DA3) and squamous cell carcinoma (SQ2 Cancer is currently viewed as a cell cycle disease. Strategies to treat malignancies are thus shifting from toxic chemotherapy to agents that switch-off positive cell replication transducers specifically or to activators of endogenous negative cell cycle regulators (p53, p21 waf1 , Kip and INK families of proteins). 1 The feasibility of the novel approach is exemplified by recent success in achieving clinical remissions by Imatinib Mesylate (Gleevec), a rationally designed catalytic domain inhibitor of Abl, c-Kit and PDGFR tyrosine kinases. [2][3][4] Other agents such as the cyclin-dependent kinase inhibitors, flavopiridol, 7-hydroxystaurosporine (UCN-01) and staurosporine are at different phases of clinical development. 5,6 Additional attractive targets for intracellular signaling inhibition are modulators of the PKC family of isoenzymes. Perihydroxylated perylene quinones constitute a unique class of photoactivated inhibitors of ser/thr kinases. In this group, hypericin (HY) has been reported to inhibit PKC, 7,8 Erk1/2 kinases and also epidermal growth factor receptor tyrosine kinase. 9 -11 Most of these signaltransduction inhibitory activities of hypericin have been attributed to the photodynamic properties of the compound that were achieved when HY was excited by light at wavelengths absorbed by the molecule. 11 However, recent observations suggest that HY, in addition to its light-dependent anticancer activities, 12 possesses potent anticancer activities and ability to inhibit different signal transduction pathways also in the absence of light activation (dark effects). [13][14][15] We recently demonstrated that the newly identified anti-cancer activities of HY in the dark differ from the well-characterized light-induced effects of the compound in kinetics, modes of tumor cell death and their underling mechanisms. 13 Cell death induction by HY with light occurs rapidly. Within hours after light irradiation, cells undergo apoptosis, or if the light dose is high, also necrosis. In the dark, on the other hand, tumor cell exposure to HY is required for at least 48 hr in order to inhibit cell proliferation. At higher HY concentrations (Ͼ 10 M), the compound killed the tumor cells in the dark via mitotic cell death. 16 Mitotic cell death is a process observed in cancer cells following treatment with different chemotherapeutic agents as well as radiotherapy. The phenomenon is characterized by cells accumulation at G 2 /M, uncoupling of apoptosis, increased cell volume and multinucleation leading to cell death. 17 Although the precise mechanisms leading to mitotic cell death are not fully understood, we have recently identified processes by wh...

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“…Protoporphyrin IX is formed as the penultimate step of the haem biosynthetic pathway. The promise of this photosensitizer stems from reports that PPIX accumulates to a greater extent in malignant compared to normal tissue after administration of δ-aminolaevulinic acid (δ-ALA) (Dailey and Smith, 1984;van Hillegersberg et al, 1992;Malik et al, 1995). Although the basis for its concentration in tumour tissue is not known, this observation is being exploited in the use of δ-ALA in PDT.…”

mentioning

confidence: 99%

δ-Aminolaevulinic acid-induced photodynamic therapy inhibits protoporphyrin IX biosynthesis and reduces subsequent treatment efficacy in vitro

Havens

Nguyen

et al. 1999

Br J Cancer

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Summary Recently, considerable interest has been given to photodynamic therapy of cancer using δ-aminolaevulinic acid to induce protoporphyrin IX as the cell photosensitizer. One advantage of this modality is that protoporphyrin IX is cleared from tissue within 24 h after δ-aminolaevulinic acid administration. This could allow for multiple treatment regimens because of little concern regarding the accumulation of the photosensitizer in normal tissues. However, the haem biosynthetic pathway would have to be fully functional after the first course of therapy to allow for subsequent treatments. Photosensitization of cultured R3230AC rat mammary adenocarcinoma cells with δ-aminolaevulinic acid-induced protoporphyrin IX resulted in the inhibition of porphobilinogen deaminase, an enzyme in the haem biosynthetic pathway, and a concomitant decrease in protoporphyrin IX levels. Cultured R3230AC cells exposed to 0.5 mM δ-aminolaevulinic acid for 27 h accumulated 6.07 × 10 -16 mol of protoporphyrin IX per cell and had a porphobilinogen deaminase activity of 0.046 fmol uroporphyrin per 30 min per cell. Cells cultured under the same incubation conditions but exposed to 30 mJ cm -2 irradiation after a 3-h incubation with δ-aminolaevulinic acid showed a significant reduction in protoporphyrin IX, 2.28 × 10 -16 mol per cell, and an 80% reduction in porphobilinogen deaminase activity to 0.0088 fmol uroporphyrin per 30 min per cell. Similar effects were evident in irradiated cells incubated with δ-aminolaevulinic acid immediately after, or following a 24 h interval, post-irradiation. There was little gain in efficacy from a second treatment regimen applied within 24 h of the initial treatment, probably a result of initial metabolic damage leading to reduced levels of protoporphyrin IX. These findings suggest that a correlation may exist between the δ-aminolaevulinic acid induction of porphobilinogen deaminase activity and the increase in intracellular protoporphyrin IX accumulation.

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Topical application of 5-aminolevulinic acid, DMSO and EDTA: protoporphyrin IX accumulation in skin and tumours of mice

Cited by 131 publications

References 13 publications

Kinetics and localisation of PpIX fluorescence after topical and systemic ALA application, observed in skin and skin tumours of UVB-treated mice

Kinetics and localisation of PpIX fluorescence after topical and systemic ALA application, observed in skin and skin tumours of UVB-treated mice

Antimetastatic activity of the photodynamic agent hypericin in the dark

δ-Aminolaevulinic acid-induced photodynamic therapy inhibits protoporphyrin IX biosynthesis and reduces subsequent treatment efficacy in vitro

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