Hydroporphyrins of the <i>meso</i>-tetra(hydroxyphenyl)porphyrin series as tumour photosensitizers

Bonnett, Raymond; White, Ralph deVere; Winfield, U J; Berenbaum, M. C.

doi:10.1042/bj2610277

Cited by 307 publications

(180 citation statements)

References 17 publications

(17 reference statements)

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“…Meta-tetra(hydroxyphenyl)chlorin (mTHPC, Foscan s ) is a second-generation photosensitiser (Bonnett et al, 1989) that appears to be one of the most effective sensitisers studied to date (Dougherty et al, 1998). Recently, a regulatory approval was granted for the Foscan s -PDT palliative treatment of head and neck cancers.…”

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confidence: 99%

Endoplasmic reticulum and Golgi apparatus are the preferential sites of Foscan® localisation in cultured tumour cells

et al. 2003

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Intracellular photosensitiser localisation significantly influences the mechanism of response to photodynamic therapy (PDT), since the primary sites of damage are closely related to the specific sensitiser distribution. Foscan s subcellular localisation in the MCF-7 human adenocarcinoma cell line has been studied by means of confocal microscopy and microspectrofluorometry. The fluorescence topographic profiles recorded after cells costained with Foscan s and organelle-specific fluorescent probes revealed that Foscan s presents low localisation in lysosomes and a weak accumulation in mitochondria. Alternatively, the Foscan s fluorescence topographic profile turned out to colocalise perfectly with that obtained for the endoplasmic reticulum (ER) and the Golgi apparatus. The patterns of fluorescence derived from confocal microscopy studies were consistent with predominant localisation of Foscan s in these organelles. Furthermore, evaluation of enzymatic activity of selected organelles immediately after laser light irradiation (650 nm) indicated the Golgi apparatus and ER as the primary damaged sites resulting from Foscan s -mediated PDT in the MCF-7 cell line. To our knowledge, this is the first study to demonstrate unambiguously that the ER and the Golgi apparatus are preferential sites of Foscan s accumulation.

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confidence: 99%

Endoplasmic reticulum and Golgi apparatus are the preferential sites of Foscan® localisation in cultured tumour cells

et al. 2003

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“…This figure takes into account the drug dose required (0.15 mg kg À1 compared to 10 mg kg À1 for PII) and the lower light doses necessary (30 J cm À1 rather than 150 J cm À1 ) to produce similar PDT results. However, the reason for this effectiveness remains unresolved even considering the advantageous photoproperties of increased molar absorption coefficient and a favourable shift in the wavelength maximum (652 nm rather than 630 nm) (Bonnett et al, 1989).…”

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Photodynamic therapy effect of m-THPC (Foscan®) in vivo: correlation with pharmacokinetics

2003

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m-Tetra(hydroxyphenyl)chlorin (m-THPC, Foscan, Temoporfin) has an unusually high photodynamic efficacy which cannot be explained by its photochemical properties alone. In vivo interactions are therefore of critical importance in determining this high potency. The pharmacokinetics of m-THPC in a rat tumour model was determined using 14 C m-THPC in an LSBD 1 fibrosarcoma implanted into BDIX rats. The photodynamic therapy (PDT) efficacy was determined at different drug administrations to light intervals and correlated with the tumour and plasma pharmacokinetic data. The plasma pharmacokinetics of m-THPC can be interpreted by compartmental analysis as having three half-lives of 0.46, 6.91 and 82.5 h, with a small initial volume of distribution, suggesting retention in the vascular compartment. Tissues of the reticuloendothelial system showed high accumulation of m-THPC, particularly the liver. PDT efficacy of m-THPC over the same time course seemed to exhibit two peaks of activity (2 and 24 h), in terms of tumour growth delay with the peak at 24 h postinjection correlating to the maximum tumour concentration. Investigation on tumour cells isolated from m-THPC-treated tumours suggested that the peak PDT activity at 2 h represents an effect on the vasculature while the peak at 24 h shows a more direct response. These results indicate that the in vivo PDT effect of m-THPC occurs via several mechanisms. British Journal of Cancer (2003) Photodynamic therapy (PDT) is becoming accepted as an alternative to conventional cancer treatments for certain indications and other nononcological conditions. It is based on a tumour accumulation of a photosensitiser, which, when activated by light, results in tumour destruction via reactive oxygen species (Ochsner, 1997). The selectivity of PDT relies upon the targeting of the light delivery in combination with the accumulation/retention of the photosensitiser in malignant tissue. The time interval between photosensitiser administration and light delivery is crucial for the optimal clinical efficacy of PDT. The distribution of the photosensitiser both in the tumour as a whole and throughout the tumour compartments is dependent on this interval as well as in vivo interactions that affect photosensitiser aggregation, delivery and uptake (Boyle and Dolphin, 1996). m-Tetra (hydroxyphenyl)chlorin (m-THPC), a second-generation photosensitiser, has already been shown to be more potent than Photofrin (PII). It has been suggested that it is up to 200 times more powerful (Van Geel et al, 1995;Ball et al, 1999). This figure takes into account the drug dose required (0.15 mg kg À1 compared to 10 mg kg À1 for PII) and the lower light doses necessary (30 J cm À1 rather than 150 J cm À1 ) to produce similar PDT results. However, the reason for this effectiveness remains unresolved even considering the advantageous photoproperties of increased molar absorption coefficient and a favourable shift in the wavelength maximum (652 nm rather than 630 nm) (Bonnett et al, 1989).Preclinical studies have alread...

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“…Currently, one of the photosensitizers that is attracting particular interest is meta-tetrahydroxyphenyl chlorin (mTHPc), which was developed at Queen Mary & Westfield College, London, UK, (Berenbaum et al, 1986(Berenbaum et al, , 1993Bonnett et al, 1989) and was used in the present study. The tumoricidal effects have been studied in BALBc nude mice bearing human malignant mesothelioma xenografts (Chevretton et al, 1992;Ris et al, 1993).…”

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Photodynamic therapy of a transplanted pancreatic cancer model using meta-tetrahydroxyphenylchlorin (mTHPC)

MIkvy

Messman²,

MacRobert³

et al. 1997

Br J Cancer

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Summary Pancreatic cancer is difficult to treat, even for tumours localized to the pancreas. Photodynamic therapy (PDT) is a non-thermal technique for producing localized tissue necrosis with light after prior administration of a photosensitizing drug and it could have a role in the local treatment of these cancers. We studied PDT in a transplanted cancer in the hamster pancreas using the photosensitizer mTHPC (metatetrahydroxyphenylchlorin). Fluorescence microscopy showed maximum levels of mTHPC in normal pancreas 2-4 days after sensitization and in tumour at 4-5 days. For PDT, animals were given 0.1 or 0.3 mg kg-' mTHPC and the tumour was treated at laparotomy 2 or 4 days later with red light (50 J at 650 nm, continuous or fractionated) delivered via a single fibre touching the tumour surface. The maximum zone of tumour necrosis (seen 3 days after PDT) was 8.7 mm in diameter with continuous irradiation, increasing to 12.4 mm with light fractionation (four equal fractions with 3 min between fractions). The main complication was sealed duodenal perforation, seen in 3 of 16 animals, probably due to inadequate shielding of the duodenum from the light. The duodenal problems seen in hamsters are unlikely to cause trouble in the much thicker human duodenum. PDT tumour necrosis in this animal model has now been shown with a range of photosensitizers, but mTHPC is attractive as it is likely to produce the largest volumes of necrosis around each treatment point with short light exposure times. This technique could have a role in the treatment of localized cancers of the pancreas in patients unsuitable for surgery and can now be considered for preliminary clinical trials.

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Hydroporphyrins of the meso-tetra(hydroxyphenyl)porphyrin series as tumour photosensitizers

Cited by 307 publications

References 17 publications

Endoplasmic reticulum and Golgi apparatus are the preferential sites of Foscan® localisation in cultured tumour cells

Endoplasmic reticulum and Golgi apparatus are the preferential sites of Foscan® localisation in cultured tumour cells

Photodynamic therapy effect of m-THPC (Foscan®) in vivo: correlation with pharmacokinetics

Photodynamic therapy of a transplanted pancreatic cancer model using meta-tetrahydroxyphenylchlorin (mTHPC)

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