RESUMO
Photoactivated hypericin produces singlet oxygen and superoxide anion radical; however, the intracellular events contributing to toxicity are unknown. Clonogenic assays of oxygen-dependent hypericin phototoxicity to EMT6 cells have previously shown that 0.5 microM hypericin + 1.5 J cm(-2) fluorescent light is non-toxic and that 1.0 microM hypericin + 1.5 J cm(-2) fluorescent light produces LD40 toxicity. Intracellular events leading to toxicity were revealed at these doses. Lactate dehydrogenase leakage was elevated for both 0.5 microM and 1.0 microM hypericin + light immediately following irradiation. While values eventually returned to control levels for 0.5 microM hypericin + light, leakage increased over time for 1.0 microM hypericin indicating reversible and irreversible toxicity, respectively. Increases in lipid and protein oxidation were measured immediately following irradiation; however, these parameters return to control levels within 0.5 h for both doses. Both total cellular ATP levels and cellular respiration were depressed by approximately 50% of control values for 1.0 microM hypericin + light. These values were unchanged for 0.5 microM hypericin + light. Along with previously reported data demonstrating that light-activated hypericin can inhibit mitochondial succinoxidase in beef heart mitochondria in vitro, these data support oxidative stress-initiated mitochondrial damage as a key target in hypericin phototoxicity.
Assuntos
Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/efeitos da radiação , Mitocôndrias/efeitos dos fármacos , Perileno/análogos & derivados , Trifosfato de Adenosina/análise , Animais , Antracenos , Membrana Celular/efeitos dos fármacos , Membrana Celular/efeitos da radiação , Respiração Celular/efeitos dos fármacos , Respiração Celular/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta a Droga , Feminino , Líquido Intracelular/química , L-Lactato Desidrogenase/análise , Luz , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos da radiação , Neoplasias Mamárias Animais , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos da radiação , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Perileno/toxicidade , Fármacos Fotossensibilizantes/toxicidade , Proteína Quinase C/antagonistas & inibidores , Proteínas/efeitos dos fármacos , Proteínas/metabolismo , Proteínas/efeitos da radiação , Substâncias Reativas com Ácido Tiobarbitúrico/análise , Fatores de Tempo , Células Tumorais CultivadasRESUMO
Stereotactic linear accelerator (linac) radiosurgery has been in operation in the West Midlands since 1987, the first of its kind in the United Kingdom. Forty two patients with high-flow cerebral arteriovenous malformations have been treated, 26 of whom have been followed up. Angiography one year after treatment showed that five lesions were obliterated, 11 were reduced in size and/or flow rate and 10 were unchanged. Overall results show that nine out of 10 patients reviewed at 24 months had total obliteration. Three patients had complications; one has fully recovered, one died of an unrelated cause at 36 months and the other died from recurrent haemorrhage at nine months. Two patients had recurrent non-fatal haemorrhage within 24 months of treatment; both recovered without further deficit. All patients are fit to work but eight are unemployed. Although the follow up period is short, the early results indicate a success rate similar to those published by others using linac radiosurgery.