PURPOSE:A phase II trial of Photofrin-mediated i.p. photodynamic therapy shown in a previous report limited efficacy and significant acute, but not chronic, toxicity. A secondary aim of this trial and the subject of this report is to determine Photofrin uptake in tumor and normal tissues.
EXPERIMENTAL DESIGN:Patients received Photofrin, 2.5 mg/kg, i.v., 48 hours before debulking surgery. Photofrin uptake was measured by spectroflurometric analysis of drug extracted from tumor and normal tissues removed at surgery. Differences in drug uptake among these tissues were statistically considered using mixed-effects models.
RESULTS:Photofrin concentration was measured in 301 samples collected from 58 of 100 patients enrolled on the trial. In normal tissues, drug uptake significantly (P<0.0001) differed as a function of seven different tissue types. In the toxicity-limiting tissue of intestine, the model-based mean (SE) Photofrin level was 2.70 ng/mg (0.32 ng/mg) and 3.42 ng/mg (0.24 ng/mg) in full-thickness large and small intestine, respectively. In tumors, drug uptake significantly (P=0.0015) differed as a function of patient cohort: model-based mean Photofrin level was 3.32 to 5.31 ng/mg among patients with ovarian, gastric, or small bowel cancer; 2.09 to 2.45 ng/mg among patients with sarcoma and appendiceal or colon cancer; and 0.93 ng/mg in patients with pseudomyxoma. Ovarian, gastric, and small bowel cancers showed significantly higher Photofrin uptake than full-thickness large and/or small intestine. However, the ratio of mean drug level in tumor versus intestine was modest (
译文
目的：Photofrin介导的i.p.的II期临床试验。先前报告中显示的光动力疗法疗效有限，且具有明显的急性毒性，但非慢性毒性。该试验和本报告主题的第二个目的是确定肿瘤和正常组织中的光敏蛋白摄取量。
实验设计：患者在减容手术前48小时接受静脉注射2.5 mg / kg的Photofrin。通过分光光度法对从肿瘤和手术中切除的正常组织中提取的药物进行分光光度法分析来测量光蛋白的摄取。使用混合效应模型从统计学上考虑了这些组织之间的药物吸收差异。
结果：在从该试验的100名患者中的58名患者中收集的301个样品中测量了光敏蛋白的浓度。在正常组织中，药物吸收显着不同（P <0.0001），是七种不同组织类型的函数。在肠道毒性限制组织中，全厚度大肠和小肠中基于模型的平均（SE）Photofrin水平分别为2.70 ng / mg（0.32 ng / mg）和3.42 ng / mg（0.24 ng / mg），分别。在肿瘤中，药物摄取随患者队列的不同而有显着差异（P = 0.0015）：卵巢癌，胃癌或小肠癌患者中基于模型的平均Photofrin水平为3.32至5.31 ng / mg。肉瘤，阑尾或结肠癌患者中2.09至2.45 ng / mg；假性粘液瘤患者为0.93 ng / mg。与全厚度大肠和/或小肠相比，卵巢癌，胃癌和小肠癌的Photofrin摄取量明显更高。然而，肿瘤与肠道中平均药物水平的比率是中等的（<或= 2.31）。
结论：在肿瘤与腹膜腔正常组织之间的光敏蛋白吸收中发现了一些选择性，但是相对于毒性受限的正常组织（肠）而言，药物吸收的绝对差异很小。先前已经报道过，药物选择性的这种狭窄差异可能导致治疗应用中的狭窄窗口。
实验设计：患者在减容手术前48小时接受静脉注射2.5 mg / kg的Photofrin。通过分光光度法对从肿瘤和手术中切除的正常组织中提取的药物进行分光光度法分析来测量光蛋白的摄取。使用混合效应模型从统计学上考虑了这些组织之间的药物吸收差异。
结果：在从该试验的100名患者中的58名患者中收集的301个样品中测量了光敏蛋白的浓度。在正常组织中，药物吸收显着不同（P <0.0001），是七种不同组织类型的函数。在肠道毒性限制组织中，全厚度大肠和小肠中基于模型的平均（SE）Photofrin水平分别为2.70 ng / mg（0.32 ng / mg）和3.42 ng / mg（0.24 ng / mg），分别。在肿瘤中，药物摄取随患者队列的不同而有显着差异（P = 0.0015）：卵巢癌，胃癌或小肠癌患者中基于模型的平均Photofrin水平为3.32至5.31 ng / mg。肉瘤，阑尾或结肠癌患者中2.09至2.45 ng / mg；假性粘液瘤患者为0.93 ng / mg。与全厚度大肠和/或小肠相比，卵巢癌，胃癌和小肠癌的Photofrin摄取量明显更高。然而，肿瘤与肠道中平均药物水平的比率是中等的（<或= 2.31）。
结论：在肿瘤与腹膜腔正常组织之间的光敏蛋白吸收中发现了一些选择性，但是相对于毒性受限的正常组织（肠）而言，药物吸收的绝对差异很小。先前已经报道过，药物选择性的这种狭窄差异可能导致治疗应用中的狭窄窗口。
