Chalcogenapyrylium dyes as dual-action sensitizers for photodynamic therapy.
Cytochrome c oxidase activity in isolated tumor mitochondria was inhibited by exposure to 570-800 nm of light after addition of cationic dye 1. The alteration in enzyme activity is a consequence of the formation of the highly reactive oxygen species, singlet oxygen, a photochemical product resulting from the irradiation (770 nm of light) of dye 1 in the presence of oxygen. The oxidation of dye 1 by singlet oxygen produces dye 2. Irradiation of mitochondrial suspensions treated with 10(-5) M solutions of dye 2 with 489 +/- 5 nm of light also caused inhibition of cytochrome c oxidase activity, but the addition of scavengers of singlet oxygen, hydrogen peroxide, superoxide, and hydroxyl radical did not prevent the observed inhibition. Similarly, lowering the atmospheric oxygen concentration to 3% had no effect on mitochondrial inhibition. In solution, photoreduction of dye 2 occurred at an increased rate in the presence of 0.01 M tryptophan. ESR studies of dye 2 with 5,5 dimethyl-1-pyrroline-N-oxide (DMPO) (0.1 M) and added tryptophan (0.01 M) suggested the photoproduction of hydroxyl radicals as a possible mechanism for its photodynamic action. We interpret the data as indicating the possibility that after the photooxidative transformation of dye 1 to dye 2, a second mechanism becomes operative for further photodynamic inhibition of enzyme activity. The in vivo or in vitro conversion of dye 1 to dye 2 would allow dye 1 to function as a novel, dual-action photosensitizer.
Detty
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MR
Corporate Research Laboratories, Eastman Kodak Company, Rochester, New York 14650.
Merkel
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PB
Gibson
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Hilf
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D000818:Animals; D004396:Coloring Agents / Q000737:chemistry / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors; D005260:Female; D016166:Free Radical Scavengers; D066298:In Vitro Techniques; D008325:Mammary Neoplasms, Experimental / Q000648:ultrastructure; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D010084:Oxidation-Reduction; D010777:Photochemistry; D010782:Photolysis; D017319:Photosensitizing Agents / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D014364:Tryptophan / Q000737:chemistry
D004396:Coloring Agents; D016166:Free Radical Scavengers; D017319:Photosensitizing Agents; D014364:Tryptophan; D003576:Electron Transport Complex IV