title: Photodynamic therapy with verteporfin in the radiation-induced fibrosarcoma-1 tumor causes enhanced radiation sensitivity.
abstract: Photodynamic therapy (PDT) with verteporfin (lipid form of benzoporphyrin derivative,benzoporphyrin derivative monoacid ring A) was used to treat radiation-induced fibrosarcoma tumors before X-ray treatment. When verteporfin was injected 3 h before light irradiation, the tumor partial pressure of oxygen (pO(2)) rose from a pretreatment value of 2.8 +/- 1 to 15.2 +/- 6.9 mm Hg immediately after light application was complete (P = 0.048). When the optical irradiation was given 15 min after verteporfin injection, the tumor pO(2) decreased slightly after treatment [i.e., 6.8 +/- 1.6 mm Hg (pretreatment) versus 4.1 +/- 0.3 mm Hg (posttreatment)], whereas control tumor pO(2) did not change significantly. In vitro study of the cellular oxygen consumption rate before and after PDT treatment indicated that the consumption rate decreased linearly with delivered optical dose and quantitatively matched the loss of cell viability as measured by a mitochondrial tetrazolium assay. Doppler measurements show that red cell flux is still patent immediately after treatment, indicating that oxygen should still be delivered to the tumor. Computational simulations of the oxygen supply from the vessels and the consumption from mitochondrial activity confirmed that if oxygen consumption is decreased in the presence of unhindered blood flow, the tumor oxygenation should rise, and the hypoxic fraction of the tumor should decrease. Combination treatments with PDT delivered (100 J/cm(2) optical dose, with 1 mg/kg benzoporphyrin derivative monoacid ring A injected 3 h before treatment) after radiation treatment (10 Gy from 300 keV source) were compared with PDT delivered simultaneously with radiation. Tumor regrowth assay showed that the delays to reach double the tumor volume for PDT alone and radiation alone were 2.7 +/- 1.6 and 3.2 +/- 1.7 days, respectively. When radiation was given before PDT, the delay was 5.4 +/- 1.4 days, and when PDT was given at the same time as radiation, the delay was 8.1 +/- 1.5 days. This observation indicates that the combined effect in the latter case was greater than additive (P = 0.049).
authors.affiliation: Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire 03755, USA. pogue@dartmouth.edu
authors.forename: Brian W
authors.initials: BW
authors.lastname: Pogue
authors.forename: Julia A
authors.initials: JA
authors.lastname: O'Hara
authors.forename: Eugene
authors.initials: E
authors.lastname: Demidenko
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Wilmot
authors.forename: Isak A
authors.initials: IA
authors.lastname: Goodwin
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.forename: Harold M
authors.initials: HM
authors.lastname: Swartz
authors.forename: Tayyaba
authors.initials: T
authors.lastname: Hasan
mesh_terms: D000818:Animals; D001481:Basal Metabolism / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D003198:Computer Simulation; D005260:Female; D005354:Fibrosarcoma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D051379:Mice; D008809:Mice, Inbred C3H; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010313:Partial Pressure; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000494:pharmacology*; D011166:Porphyrins / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects*; D000077362:Verteporfin
chemical_list: D017319:Photosensitizing Agents; D011166:Porphyrins; D000077362:Verteporfin; D010100:Oxygen