Cutaneous phototoxic occurrences in patients receiving Photofrin®

Dougherty, Thomas J.; Cooper, Mary Anne; Mang, Thomas S.

doi:10.1002/lsm.1900100514

Cited by 286 publications

(130 citation statements)

References 5 publications

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“…Light activation of the photosensitiser results in the production of reactive oxygen species that subsequently act as the cytotoxic agent (Weishaupt et al, 1976). The advantage of PDT over conventional therapies is that it is relatively non-invasive and has limited toxicity (Dougherty et al, 1990). Toxicity is minimised by the ability to restrict the light activation to the tumour site and increased accumulation of the photosensitiser within tumour tissue compared with unaffected tissue (Moan & Berg, 1992).…”

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confidence: 99%

Evidence for low-density lipoprotein receptor-mediated uptake of benzoporphyrin derivative

Allison

Ph²,

Levy³

1994

Br J Cancer

152

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Summary Plasma lipoproteins, such as low-density lipoprotein (LDL), have been proposed to enhance the delivery of hydrophobic photosensitisers to malignant tissue since tumour cells have been shown to have increased numbers of LDL receptors. We have investigated the role of this receptor in the cellular accumulation of the photosensitiser benzoporphyrin derivative (BPD). We observed that: (1) [`4C]BPD-LDL accumulation by LDL receptor-negative fibroblast cell lines was insignificant compared with normal cell lines; (2) there was no evidence that BPD dissociated from LDL during incubation with the cells; and (3) chemical acetylation of LDL markedly decreased the uptake of ['4C]BPD-LDL. We conclude, therefore, that virtually all of the photosensitiser accumulated by the cells was due to specific binding and internalisation via the LDL receptor. Subsequent in vivo studies in M-1 (methylcholanthrene-induced rhabdomyosarcoma) tumour-bearing DBA/2J mice showed that tumour accumulation of BPD associated with native LDL was significantly (P<0.01) enhanced over that of acetyl-LDL-associated BPD. These results indicate that the LDL receptor is responsible for the accumulation of LDL-associated BPD both in vitro and in vivo. Thus, utilisation of this delivery system may provide for improvements in photodynamic therapy in clinical practice.

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confidence: 99%

Evidence for low-density lipoprotein receptor-mediated uptake of benzoporphyrin derivative

Allison

Ph²,

Levy³

1994

Br J Cancer

152

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“…The main problem with these first-generation photosensitizers is that of prolonged skin photosensitivity. Phototoxic incidences of 20-40% have been reported during follow-up of patients having received Photofrin, with a mean duration of skin photosensitivity exceeding 6 weeks (Dougherty et al, 1990).The use of 5-aminolaevulinic acid (ALA) represents a different strategy in the administration of photosensitizers. ALA itself is not the photo-active drug, but rather it induces, in situ, the synthesis of a pure endogenous porphyrin called protoporphyrin IX (PpIX).…”

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confidence: 99%

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confidence: 99%

Effect of photodynamic therapy in combination with ionizing radiation on human squamous cell carcinoma cell lines of the head and neck

2000

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Photodynamic therapy (PDT) is a method for the treatment of cancer that involves the administration of systemic or topical photosensitizing drugs that are preferentially taken up by the tumour and then activated in the presence of light to cause tissue destruction (Dougherty, 1988). Photodynamic therapy works by the generation of singlet oxygen that results in damage to cell membrane structures, microvascular ischaemia, and tissue necrosis. Numerous clinical trials of photodynamic therapy have been conducted over the past decade and PDT has been approved for clinical use in recurrent bladder carcinomas, obstructing oesophageal tumours, and early carcinomas of the bladder, oesophagus, stomach, and tracheobronchial tree. PDT has also been shown to provide curative treatment of early carcinomas of the head and neck, including the oral cavity, pharynx, and larynx (Biel, 1995;Feyh, 1996). Initially PDT was tested in advanced cancers of the head and neck that were untreatable or refractory to conventional therapy, however these trials produced only limited success (Schuller et al, 1984;Wile et al, 1984). A recent retrospective review of the clinical data available for the treatment of head and neck neoplasia using photodynamic therapy indicated that complete response rates of 89.5% are achievable for early squamous cell carcinoma of the head and neck (Biel, 1998). Based on a range of photosensitizers and treatment modalities, cure rates of 95% and 80% were obtained for carcinoma in situ and T1 squamous cell carcinoma of the vocal chord and oral cavity/tongue respectively (follow up 70 months) (Biel, 1998).Most of the available photosensitizers, until recently, have been mixtures of porphyrins such as haematoporphyrin derivative and Photofrin (Quadralogic Technologies, Vancouver, Canada). The main problem with these first-generation photosensitizers is that of prolonged skin photosensitivity. Phototoxic incidences of 20-40% have been reported during follow-up of patients having received Photofrin, with a mean duration of skin photosensitivity exceeding 6 weeks (Dougherty et al, 1990).The use of 5-aminolaevulinic acid (ALA) represents a different strategy in the administration of photosensitizers. ALA itself is not the photo-active drug, but rather it induces, in situ, the synthesis of a pure endogenous porphyrin called protoporphyrin IX (PpIX). The formation of PpIX forms part of the haem synthesis pathway and all nucleated cells that use oxidative metabolism are probably capable of forming this photosensitizer. However, malignant tissue appears to preferentially accumulate PpIX, forming the basis of photodynamic therapy in cancer (Battle, 1993;Kennedy and Pottier, 1994). Intravenous ALA is rapidly cleared from the body, with no PpIX fluorescence within the skin or other body organs detectable after 24 h (Kennedy et al, 1991).Because of this reduced phototoxicity and excellent tumour localizing properties, ALA has been used with great success for the treatment of several neoplastic diseases, particularly of the skin, b...

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“…The currently clinically approved photosensitizers [haematoporphyrin derivative (HPD) and its purified components] are powerful sensitizers but with low tumour selectivity and prolonged skin photosensitivity (Dougherty et al, 1990). In addition to tumour cell-directed necrosis induced by PDT, HPD additionally accumulates in endothelial cells (Leunig et al, 1994), allowing destruction of the tumour vascular system (van Geel et al, 1994).…”

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Influence of a haematoporphyrin derivative on the protoporphyrin IX synthesis and photodynamic effect after 5-aminolaevulinic acid sensitization in human colon carcinoma cells

Messmann

Geisler²,

Groß³

et al. 1997

Br J Cancer

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Summary Haematoporphyrin derivatives (HPDs) are potent sensitizers in photodynamic therapy (PDT), associated with prolonged skin photosensitivity. 5-Aminolaevulinic acid (5-ALA), a natural precusor of haem, is converted intracellularly into the photosensitive agent protoporphyrin IX (PPIX), causing direct cytotoxicity after laser light irradiation but limited skin photosensitivity over 1-2 days and higher tumour selectivity. Unfortunately, the use of 5-ALA in PDT has been shown to cause only superficial tissue necrosis. Therefore, a combination of HPD and 5-ALA could be of great clinical value in the treatment of tumours if a synergistic effect of both sensitizers on tumour cell necrosis with less skin photosensitivity could be demonstrated. Human colon adenocarcinoma cells (HT-29) were cultured with either HPD or 5-ALA alone, simultaneously for 24 h with 5-ALA and HPD or in succession with 5-ALA (18 h) followed by HPD (6 h at different concentrations. Intracellular PPIX concentrations were determined by high-performance thin-layer chromatography. Furthermore, PDT was performed with an incoherent light source (X = 580-740 nm) using a light dose of 30 J cm-2 and an output power of 40 mW cm-2. The intracellular PPIX concentration correlated well with 5-ALA drug dose and incubation time and was highest after single 5-ALA sensitization. In the presence of HPD, either simultaneously or sequentially, PPIX decreased significantly. The PDT effect after simultaneous incubation with both sensitizers for 24 h was not superior to incubation with HPD alone. If 5-ALA incubation (18 h) was followed by HPD (6 h) cytotoxicity after PDT was higher than with either single drug. 5-ALA (80 gg ml-') led to a decrease in tumour cell viability by 40%. A similar effect could be observed when 5-ALA and HPD were sequentially combined allowing for a reduction of the 5-ALA dose from 80 gg ml-1 in the absence of HPD to 60 9g ml-' and 5,g ml-' together with 0.5,g ml-' and 2,g ml-' HPD respectively. We speculate that the enhanced PDT effect after the combined administration of 5-ALA and HPD to cultures of colon carcinoma cells should be even more impressive in the tumour in vivo, since HPD primarily targets the tumour microvasculature and secondarily tumour cells.

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Cutaneous phototoxic occurrences in patients receiving Photofrin®

Cited by 286 publications

References 5 publications

Evidence for low-density lipoprotein receptor-mediated uptake of benzoporphyrin derivative

Evidence for low-density lipoprotein receptor-mediated uptake of benzoporphyrin derivative

Effect of photodynamic therapy in combination with ionizing radiation on human squamous cell carcinoma cell lines of the head and neck

Influence of a haematoporphyrin derivative on the protoporphyrin IX synthesis and photodynamic effect after 5-aminolaevulinic acid sensitization in human colon carcinoma cells

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