Tumour-localizing properties of porphyrins in vivo studies using free and liposome encapsulated aminolevulinic acid

Fukuda, Haydée; Paredes, Sergio; Battle, Alcira

doi:10.1016/0305-0491(92)90147-j

Cited by 56 publications

(39 citation statements)

References 5 publications

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“…These results emphasise the importance of further studies on the relationship between fluorescence kinetics and optimum interval of PDT treatment of tumours and host tissues before systemic ALA-PDT can be a successful and reliable treatment modality for human studies. Furthermore, it also seems necessary to investigate whether the bioavailability of ALA can be improved by, for example, using liposomes (Fukuda et al, 1989) as a carrier system. A successful option for increasing the retention of ALA in the circulation is by administering fractionated ALA doses.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…The main advantage of using PpIX relative to other photosensitisers is the short half life of its photosensitising effects, which do not last longer than 48 h (Fukuda et al, 1992). 5-Aminolevulinic acidinduced porphyrin fluorescence may also assist in the early detection of some malignancies (Baumgartner et al, 1996).…”

Section: -Aminolevulinic Acid (Ala) Is the First Intermediate In Hemmentioning

confidence: 99%

“…Tumour explants of about 50 mg were floated in petri dishes in serum-free minimal essential Eagle's medium, supplemented with 2 mM L-glutamine and gentamycin (40 mg ml À1 ) and incubated at 371C in presence of 0.6 mM ALA or ALA derivatives for 3 h, washed with PBS and processed for porphyrin extraction, as described above. The optimal conditions for incubation and explant sizes were as determined in a previous work (Fukuda et al, 1989).…”

Section: Organ Explant Culturesmentioning

confidence: 99%

Porphyrin synthesis from ALA derivatives for photodynamic therapy. In vitro and in vivo studies

et al. 2004

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The aim of this work was to test in vitro and in vivo the efficacy of the derivatives of 5-aminolevulinic acid (ALA): hexyl-ALA (He-ALA), undecanoyl-ALA and R,S-2-(hydroximethyl)tetrahydropyranyl-ALA (THP-ALA) as pro-photosensitising agents. The compounds were assayed in a cell line derived from a murine mammary tumour, in tumour explants and after injection of the cells into mice. In vitro, undecanoyl-ALA and THP-ALA did not improve ALA efficacy in terms of porphyrin synthesis. On the other hand, half of the amount of ALA is required to obtain the same plateau amount of photosensitiser from He-ALA. However, this plateau value cannot be surpassed in spite of the four-times higher accumulation of ALA/He-ALA from the ALA derivative. This shows that He-ALA conversion to porphyrins but not He-ALA entry to the cells is limiting. Employing ionic exchange chromatography, we found that 80% of total uptake was He-ALA whereas only 20% was ALA. This suggests that the esterases, probably themselves regulated by the heme pathway, are limiting the conversion of ALA derivatives into porphyrins. A similar situation occurs with THP-ALA. Tumour explant porphyrin results correlate well with cell line data. However, i.p. injection of ALA derivatives to mice resulted in a lower porphyrin concentration in the tumour when compared to the administration of equimolar amounts of ALA, indicating that there should be retention of ALA derivatives either within the blood vessels in the initial phase of distribution and/or within the capillaries of the tumour.

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“…Several studies, both in vivo and in vitro, have reported encouraging results (Malik and Lugaci, 1987;Fukuda et al, 1989Fukuda et al, , 1992aDivaris et al, 1990;Bedwell et al, 1992;Fijan et al, 1995;Roberts and Cairnduff, 1995;Steinbach et al, 1995;Kriegmair et al, 1996). Selective endogenously generated photosensitization depends on differential cellular rates of synthesis and loss of the porphyrins.…”

mentioning

confidence: 96%

Stimulation of tetrapyrrole synthesis in mammalian epithelial cells in culture by exposure to aminolaevulinic acid

Washbrook

Fukuda²,

Battle³

et al. 1997

Br J Cancer

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Summary Tetrapyrrole synthesis in CNCM-1221 cells exposed to 0.6 mm aminolaevulinic acid (ALA) was found to be approximately linear over a 6-h period of incubation. The rate was not significantly affected by cell density over a range of 0.015 to 0.15 x 106 cells cm-2 (final cell density). Tetrapyrrole synthesis was not affected by GABA or glutamic acid in concentrations up to 6 mm and 2.72 mm respectively, suggesting that these amino acids, which are similar in structure to ALA, do not competitively inhibit the ALA uptake pathway in these cells. Pre-exposure to haem arginate (up to 100 gM) was inhibitory, presumably by suppression (through the inhibition of ALA synthase) of an endogenous component of the response. The ALA-stimulated response was not modified by co-exposure to AIA (up to 100 mg ml-'). Despite significant reduction of protein synthesis, the porphyrinogenic response of cells exposed to ALA was unaffected by cycloheximide (10 gg ml-') or actinomycin D (10 gg ml-') even when cells were preincubated with these agents for 3 h before ALA exposure. Fetal bovine serum (10%) inhibited tetrapyrrole synthesis by 30% but increased the rate of porphyrin export by cells by a factor of 1.5. The uptake of [14C]ALA was shown to be strongly influenced by the density of the cultures. In dense cultures (final cell density of approximately 0.15 x 106 cells cm-2), the ALA uptake rate was less than 0.8 compared with a maximum rate of 4.2 fmol per cell h-' at a cell density of 0.02 x 106 cells cm-2. Since tetrapyrrole synthesis is less affected than ALA uptake by cell density, the resultant discrepancy in ALA incorporation occurrng in dense cultures implies that endogenous ALA synthesis is induced in these cells. ALA uptake was not affected by cycloheximide or actinomycin D in serum-free conditions. However, fetal bovine serum decreased external ALA uptake by about 50%. This effect was abrogated by preincubation with cycloheximide.

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Tumour-localizing properties of porphyrins in vivo studies using free and liposome encapsulated aminolevulinic acid

Cited by 56 publications

References 5 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

Porphyrin synthesis from ALA derivatives for photodynamic therapy. In vitro and in vivo studies

Stimulation of tetrapyrrole synthesis in mammalian epithelial cells in culture by exposure to aminolaevulinic acid

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