The Structure of the Active Component of Hematoporphyrin Derivative

Dougherty, Thomas J.; Potter, William R.; Weishaupt, Kenneth R.

doi:10.1007/978-1-4684-4721-7_3

Cited by 129 publications

(77 citation statements)

References 2 publications

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“…The most active component of hematoporphyrin derivative is thought to be the dihematoporphyrin ether [1,2] or ester [3] or even a triether/ester [4]. Hematoporphyrin derivative is selectively retained by malignant tumors [5][6][7], and excitation with red light (630 nm) results in the photodynamic destruction of the tumor tissue.…”

Section: Introductionmentioning

confidence: 99%

Superoxide, hydrogen peroxide and singlet oxygen in hematoporphyrin derivative-cysteine, -NADH and -light systems

Buettner

Hall

1987

Biochimica et Biophysica Acta (BBA) - General Subjects

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Hematoporphyrin derivative and light in the presence of cysteine or glutathione were found to convert oxygen to superoxide and hydrogen peroxide at pH < approx. 6.5, while at pH > 6.5 no superoxide or hydrogen peroxide production was observed. However, at pH values greater than 6.5 the rate of oxygen consumption increased. This rate paralleled the acid dissociation curve of the cysteine thioi group and is consistent with the chemical quenching of tO z by cysteine. The superoxide and hydrogen peroxide formation observed below pH 6.5 appeared not to be related to the singlet oxygen production of hematoporphyrin derivative. In addition, superoxide and hydrogen peroxide production was observed with hematoporphyrin derivative and light in the presence of NADH, both above and below pH 6.5. Direct detection of singlet oxygen luminescence at 1268 nm in the hematoporphyrin derivative-light system (2HzO as solvent) revealed an apparent linear increase in the singlet oxygen emission intensity as the pZH was raised from 7.0 to 10.0. Azide efficiently quenched this observed emission. In addition, at p2H 7.4, 1 mM cysteine resulted in a 40% reduction of the singlet oxygen luminescence, while at pZH 9.4 the signal was quenched by over 95% (under the experimental conditions employed). In total, we interpret these results as consistent with the chemical quenching of to z by the ionized thiol group of cysteine.

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Section: Introductionmentioning

confidence: 99%

Superoxide, hydrogen peroxide and singlet oxygen in hematoporphyrin derivative-cysteine, -NADH and -light systems

Buettner

Hall

1987

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…Clinically, the most used sensitisers are the derivatives of haematoporphynrn (HPD). Efforts have been directed at identifying the active component and it has been variously described as dihaematoporphyrin ether (Dougherty et al, 1984) or ester (Kessel, 1985). But there are several disadvantages regarding this sensitiser, in particular cutaneous photosensitivity may last for up to 3 months.…”

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confidence: 99%

Enhancement of photodynamic therapy with 5-aminolaevulinic acid-induced porphyrin photosensitisation in normal rat colon by threshold and light fractionation studies

Messmann

Mlkvý²,

Buonaccorsi³

et al. 1995

Br J Cancer

106

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“…It is generally agreed that cytotoxicity is mediated via formation of the highly reactive oxygen species, singlet oxygen, 102, (Weishaupt et al, 1976;Gibson et al, 1984;Parker, 1987). Since the original promising clinical results utilised HpD, a crude preparation composed of at least seven different porphyrin species (Gibson et al, 1984; Kessel, 1986;Moan et al, 1987), subsequent investigations were directed towards determination of the chemical structure of the 'active component' of HpD (Moan et al, 1982;Kessel and Chou, 1983;Dougherty et al, 1984). Methods developed to purify HpD produced a porphyrin mixture enriched in the hydrophobic components, reported to be mainly dihaematoporphyrin ethers or esters (Byrne et al, 1987;Dougherty, 1987;Kessel et al, 1987).…”

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confidence: 99%

In vitro photosensitization of tumour cell enzymes by Photofrin II administered in vivo

Murant²,

Chazen³

et al. 1989

Br J Cancer

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Dougherty, 1979). After 24-72h, to allow clearance of the photosensitiser from normal tissues, the malignant lesions are exposed to visible light, usually by laser irradiation. Tumour necrosis and regression ensue from photoradiation. It is generally agreed that cytotoxicity is mediated via formation of the highly reactive oxygen species, singlet oxygen, 102, (Weishaupt et al., 1976;Gibson et al., 1984;Parker, 1987). Since the original promising clinical results utilised HpD, a crude preparation composed of at least seven different porphyrin species (Gibson et al., 1984; Kessel, 1986;Moan et al., 1987), subsequent investigations were directed towards determination of the chemical structure of the 'active component' of HpD (Moan et al., 1982;Kessel and Chou, 1983;Dougherty et al., 1984). Methods developed to purify HpD produced a porphyrin mixture enriched in the hydrophobic components, reported to be mainly dihaematoporphyrin ethers or esters (Byrne et al., 1987;Dougherty, 1987;Kessel et al., 1987). This enriched preparation, Photofrin II, is now commercially produced for clinical and laboratory studies.In our earlier studies we utilised HpD as the photosensitiser (Hilf et al., , 1984Gibson et al., 1984). Because of the complex nature of HpD, the intracellular localisation and effects of various photosensitising components relative to time after administration could differ from the pharmacokinetics that would be observed with Photofrin II. We therefore undertook a study of Photofrin II employing the same in vivo-in vitro protocol used previously for HpD (Hilf et al., 1984). In this protocol, the photosensitiser is injected into tumour-bearing animals, tumours are removed and subcellular organelles are prepared. These preparations are then exposed to visible light in vitro, and various biochemical endpoints are analysed, such as site-specific enzyme activities. One advantage of this protocol is that it takes into account any metabolism of the sensitiser by the tumour-bearing host. In this report, using Photofrin II as the photosensitiser, data are presented on the time-course and drug dose response of photosensitisation of selected mitochondrial and cytosolic enzymes in the R3230AC mammary carcinoma. Materials and methods MaterialsPhotofrin II was kindly provided by Photomedica Inc., Raritan, NJ. All other reagents were obtained from Sigma Chemical Co., St Louis, MO, unless otherwise noted. Animals and tumoursThe R3230AC mammary adenocarcinoma was maintained by subcutaneous transplantation in the axillary region of 60-80g female Fischer rats, using the sterile trochar procedure described previously (Hilf et al., 1965).Preparation of subcellular organelles from tumours For in vitro studies, tumour-bearing rats were killed 17-24 days after implantation of the R3230AC mammary adenocarcinoma. From excised tumours, mitochondria were prepared according to methods described earlier . Briefly, R3230AC tumours were removed, weighed, placed in a dish on ice in 0.9% NaCl solution and minced with scissors. Approximately 2g...

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The Structure of the Active Component of Hematoporphyrin Derivative

Cited by 129 publications

References 2 publications

Superoxide, hydrogen peroxide and singlet oxygen in hematoporphyrin derivative-cysteine, -NADH and -light systems

Superoxide, hydrogen peroxide and singlet oxygen in hematoporphyrin derivative-cysteine, -NADH and -light systems

Enhancement of photodynamic therapy with 5-aminolaevulinic acid-induced porphyrin photosensitisation in normal rat colon by threshold and light fractionation studies

In vitro photosensitization of tumour cell enzymes by Photofrin II administered in vivo

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