title: Possible in vivo mechanisms involved in photodynamic therapy using tetrapyrrolic macrocycles.
abstract: Photodynamic therapy (PDT) mediated by oxidative stress causes direct tumor cell damage as well as microvascular injury. To improve this treatment new photosensitizers are being synthesized and tested. We evaluated the effects of PDT with 5,10,15,20-tetrakis(4-methoxyphenyl)-porphyrin (TMPP) and its zinc complex (ZnTMPP) on tumor levels of malondialdehyde (MDA), reduced glutathione (GSH) and cytokines, and on the activity of caspase-3 and metalloproteases (MMP-2 and -9) and attempted to correlate them with the histological alterations of tumors in 3-month-old male Wistar rats, 180 ± 20 g, bearing Walker 256 carcinosarcoma. Rats were randomly divided into five groups: group 1, ZnTMPP+irradiation (IR) 10 mg/kg body weight; group 2, TMPP+IR 10 mg/kg body weight; group 3, 5-aminolevulinic acid (5-ALA+IR) 250 mg/kg body weight; group 4, control, no treatment; group 5, only IR. The tumors were irradiated for 15 min with red light (100 J/cm², 10 kHz, 685 nm) 24 h after drug administration. Tumor tissue levels of MDA (1.1 ± 0.7 in ZnTMPP vs 0.1 ± 0.04 nmol/mg protein in control) and TNF-α (43.5 ± 31.2 in ZnTMPP vs 17.3 ± 1.2 pg/mg protein in control) were significantly higher in treated tumors than in controls. Higher caspase-3 activity (1.9 ± 0.9 in TMPP vs 1.1 ± 0.6 OD/mg protein in control) as well as the activation of MMP-2 (P < 0.05) were also observed in tumors. These parameters were correlated (Spearman correlation, P < 0.05) with the histological alterations. These results suggest that PDT activates the innate immune system and that the effects of PDT with TMPP and ZnTMPP are mediated by reactive oxygen species, which induce cell membrane damage and apoptosis.
authors.affiliation: Department of Physiology, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania. adrianafilip33@yahoo.com
authors.forename: A G
authors.initials: AG
authors.lastname: Filip
authors.forename: S
authors.initials: S
authors.lastname: Clichici
authors.forename: D
authors.initials: D
authors.lastname: Daicoviciu
authors.forename: R M
authors.initials: RM
authors.lastname: Ion
authors.forename: C
authors.initials: C
authors.lastname: Tatomir
authors.forename: L
authors.initials: L
authors.lastname: Rogojan
authors.forename: I
authors.initials: I
authors.lastname: Opris
authors.forename: T
authors.initials: T
authors.lastname: Mocan
authors.forename: D
authors.initials: D
authors.lastname: Olteanu
authors.forename: A
authors.initials: A
authors.lastname: Muresan
mesh_terms: D000622:Aminolevulinic Acid / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis; D002279:Carcinoma 256, Walker / Q000188:drug therapy* / Q000378:metabolism; D005978:Glutathione / Q000032:analysis; D015227:Lipid Peroxidation; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D008665:Metalloporphyrins / Q000627:therapeutic use*; D018384:Oxidative Stress; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000627:therapeutic use*; D011166:Porphyrins / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: C445706:5,10,15,20-tetrakis(4-methoxyphenyl)porphyrin; D008665:Metalloporphyrins; D017319:Photosensitizing Agents; D011166:Porphyrins; D014409:Tumor Necrosis Factor-alpha; C060088:zinc tetra(4-N-methylpyridyl)porphine; D008315:Malondialdehyde; D000622:Aminolevulinic Acid; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D005978:Glutathione