Different effects of photodynamic therapy and gamma-irradiation on vascular smooth muscle cells and matrix : implications for inhibiting restenosis.
gamma-Irradiation (gamma-RT) and photodynamic therapy (PDT) are known to inhibit intimal hyperplasia. The common mechanism is that both modalities produce free radicals, but unlike gamma-RT, PDT generates them through the absorption of light by photosensitizers. The purpose of this in vitro study was to assess the differences that PDT and gamma-RT have on the fibroproliferative response after vascular injury by comparing their effects on vascular smooth muscle cells (SMCs) and on the extracellular matrix (ECM). Mitochondrial activity (tetrazolium salt), proliferation ([(3)H]thymidine incorporation), and the mechanisms of cell death (terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling [TUNEL] staining) were used to assess differences between PDT (100 J/cm(2)) and gamma-RT (10 or 20 Gy) on SMC injury. The different effects on bioregulatory molecules were investigated by quantitating the proliferation of SMCs cultured with conditioned medium and on treated ECM. PDT of SMCs reduced proliferation and mitochondrial activity (0.5+/-0.75% and 1.7+/-4.25%, respectively, P<0.0001), whereas gamma-RT of SMCs decreased cell proliferation but did not affect metabolic activity. Stimulation with calf serum of gamma-RT-treated SMCs did not affect proliferation but increased mitochondrial enzyme activity (160+/-11%, P<0.0005). The conditioned medium, derived from PDT- but not gamma-RT-treated SMCs, did not stimulate effector SMC proliferation compared with gamma-RT-treated SMCs (16+/-4.1% versus 80+/-16.8%, P<0.0001). Apoptosis was the principle cytotoxic mechanism after PDT, whereas gamma-RT cells were growth arrested but viable. PDT of the ECM reduced effector SMC proliferation compared with controls and gamma-RT cells (18+/-6.5% versus 100+/-17.7% and 84+/-8.9%, respectively, P<0.0001). These data suggest that gamma-RT and PDT may inhibit restenosis but by different mechanisms. The effects of PDT are more diverse and may result in improved outcome while avoiding the teratogenic exposure due to ionizing irradiation.
Heckenkamp
J
J
Division of Vascular Surgery of the General Surgical Services, Wellman Laboratories of Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Leszczynski
D
D
Schiereck
J
J
Kung
J
J
LaMuraglia
G M
GM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002417:Cattle; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D003251:Constriction, Pathologic; D005109:Extracellular Matrix / Q000187:drug effects* / Q000528:radiation effects*; D005720:Gamma Rays; D006133:Growth Substances / Q000378:metabolism; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000528:radiation effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects*; D010778:Photochemotherapy; D055502:Secondary Prevention
D006133:Growth Substances