This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Henderson, B. W. Articles by Morgan, J. Search for Related Content PubMed PubMed Citation Articles by Henderson, B. W. Articles by Morgan, J.

Choice of Oxygen-Conserving Treatment Regimen Determines the Inflammatory Response and Outcome of Photodynamic Therapy of Tumors

¹ Department of Cellular Stress Biology and the Photodynamic Therapy Center, ² Department of Pathology and Lab Medicine, and ³ Department of Dermatology, Roswell Park Cancer Institute, Buffalo, New York, and ⁴ Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania

The rate of light delivery (fluence rate) plays a critical role in photodynamic therapy (PDT) through its control of tumor oxygenation. This study tests the hypothesis that fluence rate also influences the inflammatory responses associated with PDT. PDT regimens of two different fluences (48 and 128 J/cm²) were designed for the Colo 26 murine tumor that either conserved or depleted tissue oxygen during PDT using two fluence rates (14 and 112 mW/cm²). Tumor oxygenation, extent and regional distribution of tumor damage, and vascular damage were correlated with induction of inflammation as measured by interleukin 6, macrophage inflammatory protein 1 and 2 expression, presence of inflammatory cells, and treatment outcome. Oxygen-conserving low fluence rate PDT of 14 mW/cm² at a fluence of 128 J/cm² yielded 70–80% tumor cures, whereas the same fluence at the oxygen-depleting fluence rate of 112 mW/cm² yielded 10–15% tumor cures. Low fluence rate induced higher levels of apoptosis than high fluence rate PDT as indicated by caspase-3 activity and terminal deoxynucleotidyl transferase-mediated nick end labeling analysis. The latter revealed PDT-protected tumor regions distant from vessels in the high fluence rate conditions, confirming regional tumor hypoxia shown by 2-(2-nitroimidazol-1[H]-yl)-N-(3,3,3-trifluoropropyl) acetamide staining. High fluence at a low fluence rate led to ablation of CD31-stained endothelium, whereas the same fluence at a high fluence rate maintained vessel endothelium. The highest levels of inflammatory cytokines and chemokines and neutrophilic infiltrates were measured with 48 J/cm² delivered at 14 mW/cm² (10–20% cures). The optimally curative PDT regimen (128 J/cm² at 14 mW/cm²) produced minimal inflammation. Depletion of neutrophils did not significantly change the high cure rates of that regimen but abolished curability in the maximally inflammatory regimen. The data show that a strong inflammatory response can contribute substantially to local tumor control when the PDT regimen is suboptimal. Local inflammation is not a critical factor for tumor control under optimal PDT treatment conditions.

This article has been cited by other articles:

				A. Lin and S. M. Hahn Photodynamic Therapy: A Light in the Darkness? Clin. Cancer Res., July 1, 2009; 15(13): 4252 - 4253. [Abstract] [Full Text] [PDF]

				E. Kabingu, A. R. Oseroff, G. E. Wilding, and S. O. Gollnick Enhanced Systemic Immune Reactivity to a Basal Cell Carcinoma Associated Antigen Following Photodynamic Therapy Clin. Cancer Res., July 1, 2009; 15(13): 4460 - 4466. [Abstract] [Full Text] [PDF]

				M. Seshadri, D. A. Bellnier, L. A. Vaughan, J. A. Spernyak, R. Mazurchuk, T. H. Foster, and B. W. Henderson Light Delivery over Extended Time Periods Enhances the Effectiveness of Photodynamic Therapy Clin. Cancer Res., May 1, 2008; 14(9): 2796 - 2805. [Abstract] [Full Text] [PDF]

				P. C. Kousis, B. W. Henderson, P. G. Maier, and S. O. Gollnick Photodynamic Therapy Enhancement of Antitumor Immunity Is Regulated by Neutrophils Cancer Res., November 1, 2007; 67(21): 10501 - 10510. [Abstract] [Full Text] [PDF]

				T. Maisch, J. Baier, B. Franz, M. Maier, M. Landthaler, R.-M. Szeimies, and W. Baumler The role of singlet oxygen and oxygen concentration in photodynamic inactivation of bacteria PNAS, April 24, 2007; 104(17): 7223 - 7228. [Abstract] [Full Text] [PDF]

				W. Liu, M. R. Baer, M. J. Bowman, P. Pera, X. Zheng, J. Morgan, R. A. Pandey, and A. R. Oseroff The Tyrosine Kinase Inhibitor Imatinib Mesylate Enhances the Efficacy of Photodynamic Therapy by Inhibiting ABCG2 Clin. Cancer Res., April 15, 2007; 13(8): 2463 - 2470. [Abstract] [Full Text] [PDF]

				B. Kosharskyy, N. Solban, S. K. Chang, I. Rizvi, Y. Chang, and T. Hasan A Mechanism-Based Combination Therapy Reduces Local Tumor Growth and Metastasis in an Orthotopic Model of Prostate Cancer. Cancer Res., November 15, 2006; 66(22): 10953 - 10958. [Abstract] [Full Text] [PDF]

				M. Triesscheijn, P. Baas, J. H. M. Schellens, and F. A. Stewart Photodynamic Therapy in Oncology Oncologist, October 1, 2006; 11(9): 1034 - 1044. [Abstract] [Full Text] [PDF]

				M. Seshadri, J. A. Spernyak, R. Mazurchuk, S. H. Camacho, A. R. Oseroff, R. T. Cheney, and D. A. Bellnier Tumor Vascular Response to Photodynamic Therapy and the Antivascular Agent 5,6-Dimethylxanthenone-4-Acetic Acid: Implications for Combination Therapy Clin. Cancer Res., June 1, 2005; 11(11): 4241 - 4250. [Abstract] [Full Text] [PDF]

				Visudyne in Minimally Classic Choroidal Neovascula Verteporfin Therapy of Subfoveal Minimally Classic Choroidal Neovascularization in Age-Related Macular Degeneration: 2-Year Results of a Randomized Clinical Trial Arch Ophthalmol, April 1, 2005; 123(4): 448 - 457. [Abstract] [Full Text] [PDF]

				W. Liu, A. R. Oseroff, and H. Baumann Photodynamic Therapy Causes Cross-linking of Signal Transducer and Activator of Transcription Proteins and Attenuation of Interleukin-6 Cytokine Responsiveness in Epithelial Cells Cancer Res., September 15, 2004; 64(18): 6579 - 6587. [Abstract] [Full Text] [PDF]