Photodynamic Therapy Using m-Tetra(Hydroxyphenyl) Chlorin: An Animal Model

Löfgren, Lennart; Ronn, A.M.; Abramson, Allan L.; Shikowitz, Mark J.; Nouri, May; Lee, Catherine J.; Batti, James; Steinberg, Bettie M.

doi:10.1001/archotol.1994.01880360051010

Cited by 44 publications

(34 citation statements)

References 14 publications

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“…This resulted in tumour necrosis up to 10 mm deep (Ris et al, 1991), and suggested that mTHPC is an efficient second-generation sensitizer for clinical application. Similar findings emerged from experimental settings of other investigators (Lofgren et al, 1994;Ma et al, 1994;van Geel et al, 1995) However, as serious PDT-related side-effects were observed in our patients, we orientated our research towards optimization of mTHPCÐPDT by changing drug-light conditions in an experimental setting with nude mice bearing human malignant mesothelioma xenografts. The tumour and tumour-free tissue that served as control were treated under the same conditions and the extent of PDT-related tumour necrosis and normal tissue injury were compared in order to assess the therapeutic ratio for each drug-light parameter.…”

supporting

confidence: 83%

“…The ability of mTHPC to produce tumour necrosis even with small light doses under clinical (Ris et al, 1991) and experimental conditions (Lofgren et al, 1994), makes this compound attractive for its use in intraoperative PDT, given the short treatment time required. However, injuries to normal tissues have been observed in experimental settings after PDT with mTHPC, especially if high drug or light doses were applied at a short drug-light interval (Ris et al, 1993a(Ris et al, , 1993bVeenhuizen et al, 1994;van Geel et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

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Photodynamic therapy with mTHPC and polyethylene glycol-derived mTHPC: a comparative study on human tumour xenografts

et al. 1999

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SummaryThe photosensitizing properties of m-tetrahydroxyphenylchlorin (mTHPC) and polyethylene glycol-derivatized mTHPC (pegylated mTHPC) were compared in nude mice bearing human malignant mesothelioma, squamous cell carcinoma and adenocarcinoma xenografts. Laser light (20 J/cm 2 ) at 652 nm was delivered to the tumour (surface irradiance) and to an equal-sized area of the hind leg of the animals after i.p. administration of 0.1 mg/kg body weight mTHPC and an equimolar dose of pegylated mTHPC, respectively. The extent of tumour necrosis and normal tissue injury was assessed by histology. Both mTHPC and pegylated mTHPC catalyse photosensitized necrosis in mesothelioma xenografts at drug-light intervals of 1-4 days. The onset of action of pegylated mTHPC seemed slower but significantly exceeds that of mTHPC by days 3 and 4 with the greatest difference being noted at day 4. Pegylated mTHPC also induced significantly larger photonecrosis than mTHPC in squamous cell xenografts but not in adenocarcinoma at day 4, where mTHPC showed greatest activity. The degree of necrosis induced by pegylated mTHPC was the same for all three xenografts. mTHPC led to necrosis of skin and underlying muscle at a drug-light interval of 1 day but minor histological changes only at drug-light intervals from 2-4 days. In contrast, pegylated mTHPC did not result in histologically detectable changes in normal tissues under the same treatment conditions at any drug-light interval assessed. In this study, pegylated mTHPC had advantages as a photosensitizer compared to mTHPC.Tissue concentrations of mTHPC and pegylated mTHPC were measured by high-performance liquid chromatography in non-irradiated animals 4 days after administration. There was no significant difference in tumour uptake between the two sensitizers in mesothelioma, adenocarcinoma and squamous cell carcinoma xenografts. Tissue concentration measurements were of limited use for predicting photosensitization in this model.

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supporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Photodynamic therapy with mTHPC and polyethylene glycol-derived mTHPC: a comparative study on human tumour xenografts

et al. 1999

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“…At drug-light intervals longer than 4 days after injection, mTHPC disappears almost completely from the vasculature and consequently vascular damage progressively decreases. The results of this study are in agreement with those reported for other types of tumours (Ris et al, 1993a;Lofgren et al, 1994;Peng et al, 1995).…”

Section: Discussionsupporting

confidence: 93%

“…These data point to the fact that the biodistribution of the dye should be evaluated for each neoplasm in its clinical context to set up an optimal drug-light interval for PDT. In recent preclinical studies, the effect of the drug-light interval on mTHPC-PDT has been reported for bulky invasive tumours such as skin papillomas and malignant mesothelioma (Ris et al, 1993b;Lofgren et al, 1994).…”

mentioning

confidence: 99%

Photodynamic therapy of early squamous cell carcinoma with tetra(m-hydroxyphenyl)chlorin: optimal drug-light interval

Andrejevic‐Blant

Hadjur²,

Ballini³

et al. 1997

Br J Cancer

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Summary The optimal drug-light interval for effective photodynamic therapy (PDT) of early squamous cell carcinomas was evaluated with tetra(m-hydroxyphenyl)chlorin (mTHPC) by means of two complementary modalities: irradiation tests and ex vivo fluorescence microscopy. A Syrian hamster cheek pouch tumour model was used in these experiments. Photodynamic therapy on both tumour-bearing and contralateral healthy cheek pouch mucosae was performed at 650 nm and 514 nm. Light doses of 12 J cm-2 were delivered at a light dose rate of 150 mW cm-2 and light doses of 80 J cm-2 were delivered at a light dose rate of 100 mW cm-2 respectively, at these two wavelengths, between 6 h and 12 days after the injection of 0.5 mg kg-' body weight mTHPC. Two histologically different types of tissue damage were observed: first, a non-selective and non-specific ischaemic vascular necrosis for the cases in which PDT took place during the first 48 h after the injection of the dye and, second, tissue-specific PDT damage, as a coagulation necrosis, when PDT took place more than 72 h after injection of the dye. The time-dependent biodistribution of mTHPC investigated by fluorescence microscopy shows a weak and non-significant difference in relative fluorescence intensities between early SCC and healthy mucosae. Up to 2 days after the injection, the drug is mainly localized in the endothelial cells of the blood vessels. After this period, the dye accumulates in the squamous epithelia with a concentration peaking at 4 days. At all time points, a weak fluorescence intensity is observed in the underlying lamina propria and striated muscle. The information obtained from these studies could well be relevant to clinical trials as it suggests that time delays between 4 and 8 days after i.v. injection should be optimal for PDT of early malignancies in hollow organs.

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“…Recently, mTHPC has shown to be a very effective photosensitizer in various tumour models and clinical trials (Ris et al, 1991;Lofgren et al, 1994;Peng et al, 1995;Dilkes et al, 1996;Grosjean et al, 1996;Mlkvy et al, 1997), with possible preferential uptake in a colon carcinoma in mice compared to liver concentrations (Whelpton et al, 1995). Furthermore, mTHPC drug and light doses needed to induce tumour necrosis are much lower than that of HpD (Berenbaum et al, 1986).…”

mentioning

confidence: 99%

Effective treatment of liver metastases with photodynamic therapy, using the second-generation photosensitizer meta-tetra(hydroxyphenyl)chlorin (mTHPC), in a rat model

et al. 1999

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SummaryThe only curative treatment for patients with liver metastases to date is surgery, but few patients are suitable candidates for hepatic resection. The majority of patients will have to rely on other treatment modalities for palliation. Photodynamic therapy (PDT) could be a selective, minimally invasive treatment for patients with liver metastases. We studied PDT in an implanted colon carcinoma in the liver of Wag/Rij rats, using the photosensitizer meta-tetra(hydroxyphenyl)chlorin (mTHPC). mTHPC tissue kinetics were studied using ex vivo extractions and in vivo fluorescence measurements. Both methods showed that mTHPC kinetics were different for liver and tumour tissue. After initial high levels at 4 h after administration (0.1 and 0.3 mg kg -1 ) mTHPC in liver tissue decreased rapidly in time. In tumour tissue no decrease in photosensitizer levels occurred, with mTHPC remaining high up to 48 h after administration. Both concentration data and fluorescence data showed an increase in tumour to liver ratios of up to 6.3 and 5.0 respectively. Illumination with 652 nm (15 J) resulted in extensive damage to tumour tissue, with necrosis of up to 13 mm in diameter. Damage to normal liver tissue was mild and transient as serum aspartate aminotransferase and alanine aminotransferase levels normalized within a week after PDT treatment. Long-term effects of mTHPC-PDT were studied on day 28 after treatment. Regardless of drug dose and drug-light interval, PDT with mTHPC resulted in complete tumour remission in 27 out of 31 treated animals (87%), with only four animals in which tumour regrowth was observed. Non-responding tumours proved to be significantly larger (P < 0.001) in size before PDT treatment. This study demonstrates that mTHPC is retained in an intrahepatic tumour and that mTHPC-PDT is capable of inducing complete tumour remission of liver tumours.

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Photodynamic Therapy Using m-Tetra(Hydroxyphenyl) Chlorin: An Animal Model

Cited by 44 publications

References 14 publications

Photodynamic therapy with mTHPC and polyethylene glycol-derived mTHPC: a comparative study on human tumour xenografts

Photodynamic therapy with mTHPC and polyethylene glycol-derived mTHPC: a comparative study on human tumour xenografts

Photodynamic therapy of early squamous cell carcinoma with tetra(m-hydroxyphenyl)chlorin: optimal drug-light interval

Effective treatment of liver metastases with photodynamic therapy, using the second-generation photosensitizer meta-tetra(hydroxyphenyl)chlorin (mTHPC), in a rat model

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