Henderson Barbara W, Gollnick Sandra O, Snyder John W, Busch Theresa M, Kousis Philaretos C, Cheney Richard T, Morgan Janet
Department of Cellular Stress Biology and the Photodynamic Therapy Center, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA.
Cancer Res. 2004 Mar 15;64(6):2120-6. doi: 10.1158/0008-5472.can-03-3513.
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/cm(2)) 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/cm(2)). 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/cm(2) at a fluence of 128 J/cm(2) yielded approximately 70-80% tumor cures, whereas the same fluence at the oxygen-depleting fluence rate of 112 mW/cm(2) yielded approximately 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/cm(2) delivered at 14 mW/cm(2) ( approximately 10-20% cures). The optimally curative PDT regimen (128 J/cm(2) at 14 mW/cm(2)) 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.
光传递速率（通量率）通过控制肿瘤氧合作用在光动力疗法（PDT）中起着关键作用。本研究检验了通量率也会影响与PDT相关的炎症反应这一假设。针对Colo 26小鼠肿瘤设计了两种不同通量（48和128 J/cm²）的PDT方案，使用两种通量率（14和112 mW/cm²）在PDT期间保持或耗尽组织氧。肿瘤氧合、肿瘤损伤的范围和区域分布以及血管损伤与通过白细胞介素6、巨噬细胞炎性蛋白1和2表达、炎性细胞的存在以及治疗结果所测量的炎症诱导相关。在128 J/cm²的通量下以14 mW/cm²的保氧低通量率进行PDT产生了约70 - 80%的肿瘤治愈率，而在112 mW/cm²的耗氧通量率下相同通量产生了约10 - 15%的肿瘤治愈率。如通过半胱天冬酶 - 3活性和末端脱氧核苷酸转移酶介导的缺口末端标记分析所示，低通量率诱导的凋亡水平高于高通量率PDT。后者揭示了在高通量率条件下远离血管的PDT保护的肿瘤区域，证实了通过2 -（2 - 硝基咪唑 - 1[H] - 基） - N -（3,3,3 - 三氟丙基）乙酰胺染色显示的区域肿瘤缺氧。低通量率下的高通量导致CD31染色的内皮消融，而相同通量在高通量率下维持血管内皮。在14 mW/cm²下递送48 J/cm²时测量到最高水平的炎性细胞因子、趋化因子和嗜中性粒细胞浸润（约10 - 20%治愈率）。最佳治愈性PDT方案（14 mW/cm²下128 J/cm²）产生的炎症最小。嗜中性粒细胞的耗竭并未显著改变该方案的高治愈率，但消除了最大炎症方案中的治愈率。数据表明，当PDT方案次优时，强烈的炎症反应可对局部肿瘤控制有显著贡献。在最佳PDT治疗条件下，局部炎症不是肿瘤控制的关键因素。
