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Photodynamic Therapy with Verteporfin in the Radiation-induced Fibrosarcoma-1 Tumor Causes Enhanced Radiation Sensitivity¹

Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire 03755 [B. W. P., I. A. G., B. C.]; Department of Diagnostic Radiology, Dartmouth Medical School, Hanover, New Hampshire 03755 [J. A. O., C. M. W., H. M. S.]; Biostatistics, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756 [E. D.]; and Wellman Laboratories of Photomedicine, Massachusetts General Hospital, Department of Dermatology, Harvard Medical School, Boston, Massachusetts 02114 [B. W. P., T. H.]

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 (pO₂) 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 pO₂ decreased slightly after treatment [i.e., 6.8 ± 1.6 mm Hg (pretreatment) versus 4.1 ± 0.3 mm Hg (posttreatment)], whereas control tumor pO₂ 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/cm² 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).