Activité photodynamique et photo blanchiment de la méta-tétrahydroxyphénylchlorine (mTHPC). Modulation prooxydante par des antioxydants phénoliques

Abstract : Photodynamic therapy (PDT) is a rapidly growing modality for the treatment of light-accessible tumors. PDT is based on administration of tumor-localizing photosensitizers, producing toxic radicals (Type 1) or singlet oxygen (Type il reaction mechanism) on illumination. Studies on the mechanism of action and photodegradation of a second-generation photosensitizer meta-tetrahydroxyphenyIchlorin (mTHPC) were conducted and used to modulate its efficacy. Spectroscopic monitoring of mTHPC photodegradation revealed preferential photobleaching of its fluorescent forms. Elimination of mTHPC fluorescent fractions by preirradiation resulted in a negligible loss of photocytotoxic activity. This suggests that aggregated mTHPC fractions may contribute to ceIl damage. Examination of in vitro mechanism of mTHPC-photosensitized cell killing revealed that this process depends entirely on the presence of molecular oxygen. Using scavengers of reactive oxygen species, we have found that mTHPC photosensitizes cell killing predominantly by Type II, singlet oxygen-mediated photodynamic reactions. Reactions ofphotoperoxidation play only a minor role in mTHPC photocytotoxicity. Cultured HT29 human colon adenocarcinoma cells effectively incorporated antioxidant a-tocopherol, whereas NIRC-5 normal human fibroblasts did not. a-Tocopherol and its water-soluble analogue Trolox enhanced photosensitized by mTHPC damage to tumor, but not to normal cells. In vivo administration of Trolox (250 mg/kg b.w.) 1.5 hour befere irradiation enhanced PDT with mTHPC in human tumour xenografts. This effect required Trolox presence on the photochemical stage. Laser flash photolysis experiments demonstrated that Trolox acted as an efficient quencher of triplet mTHPC forming mTHPC anion radicals. Kinetic considerations suggest that Trolox mediated radical pathway can work in relay with singlet oxygen one in hypoxic conditions. Our studies show that photodynamic treatment is a subject for photochemical modulation by antioxidants.
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Theses
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http://docnum.univ-lorraine.fr/prive/SCD_T_1999_0325_MELNIKOVA.pdf
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https://hal.univ-lorraine.fr/tel-01747305
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Submitted on : Thursday, March 29, 2018 - 10:56:56 AM
Last modification on : Monday, April 16, 2018 - 10:40:45 AM

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Vladislava Melnikova. Activité photodynamique et photo blanchiment de la méta-tétrahydroxyphénylchlorine (mTHPC). Modulation prooxydante par des antioxydants phénoliques. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 1999. Français. ⟨NNT : 1999NAN19914⟩. ⟨tel-01747305⟩

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