Protection against light-activated photofrin II killing of tumor cells by nitroimidazoles.
Nitroimidazoles are good quenchers of triplet state porphyrins in chemical systems, thereby inhibiting singlet oxygen formation and type II photodynamic reactions. Photobiological studies were performed with EMT-6 tumor cells in vitro utilizing Photofrin II (PII) in combination with etanidazole (ETAN), misonidazole (MISO), and trifluoromisonidazole (TF-MISO). After short-term (1 h) exposure of cells to PII, 5 mM ETAN and MISO had no effect on photoinactivation while 5 mM TF-MISO had a small but significant protective effect. When the intracellular oxygen level was equilibrated with 0.3% oxygen in the gas phase, all three nitroimidazoles produced significant photoprotection at concentrations as low as 0.3 microM. After long-term (24 h) exposure of cells to PII, all three nitroimidazoles demonstrated large photoprotective effects under both aerobic and 0.3% oxygen conditions. At equal concentrations of nitroimidazole, photoprotection was greatest for the most lipophilic compound (TF-MISO) and least effective for the most hydrophilic compound (ETAN). These studies suggest that nitroimidazoles can quench triplet state porphyrins (within cells) to reduce intracellular concentrations of singlet oxygen, the putative toxin in PII photoinactivation. In addition, after long-term exposures to PII when porphyrins have partitioned into cellular membranes and lipid environments, the lipophilicity of this class of photoprotector correlates with effectiveness in these mammalian cells.
Santus
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Museum National d'Histoire Naturelle, Laboratoire de Physicochimie de L'Adaptation, (INSERM U. 312), Paris, France.
Stobbe
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CC
McPhee
M S
MS
Chapman
J D
JD
D000818:Animals; D017323:Dihematoporphyrin Ether; D004347:Drug Interactions; D017341:Etanidazole; D006415:Hematoporphyrins / Q000494:pharmacology*; D007834:Lasers; D051379:Mice; D008920:Misonidazole / Q000031:analogs & derivatives / Q000494:pharmacology; D009593:Nitroimidazoles / Q000494:pharmacology*; D010778:Photochemotherapy; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D006415:Hematoporphyrins; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C059168:1-(2-nitro-1-imidazoyl)-3-(2,2,2-trifluoroethoxy)-2-propanol; D017341:Etanidazole; D008920:Misonidazole; D017323:Dihematoporphyrin Ether