Alexander H R, Brown C K, Bartlett D L, Libutti S K, Figg W D, Raje S, Turner E
Surgical Metabolism Section, Surgery Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, Maryland 20892, USA.
Clin Cancer Res. 1998 Oct;4(10):2357-62.
Isolated organ perfusion of the liver or extremity with tumor necrosis factor (TNF) and melphalan results in regression of bulky tumors in the majority of patients. The efficacy of TNF in this setting is not known, although data suggest that it may exert antitumor effects primarily on tumor-associated neovasculature. We studied the effects of TNF on capillary leak in liver and tumor tissue during isolated hepatic perfusion (IHP) with melphalan. Twenty-seven patients with unresectable cancer confined to the liver underwent a 60-min hyperthermic IHP using 1.5 mg/kg melphalan alone (n = 7) or with 1.0 mg of TNF (n = 20). Complete vascular isolation was confirmed in all patients using an intraoperative leak monitoring I-131 radiolabeled albumin technique. Samples of tumor and liver were collected just prior to and immediately after IHP. There was no difference in I-131 radiolabeled cpm/g of tissue (cpm) in liver versus tumor at baseline (P2 = 0.44). After IHP, I-131 albumin cpm were higher in tumor versus liver (10,999 +/- 1,976 versus 3,821 +/- 780, respectively; P2 < 0.005). However, I-131 albumin cpm in tumor were not effected by TNF (11,636 +/- 2,518 with TNF versus 9,180 +/- 2,674 without TNF; P2 = 0.59). TNF did not affect melphalan concentrations in tumor (1,883 +/- 540 ng/g versus 1,854 +/- 861 ng/g without TNF; P2 = 0.9). Capillary leak, as reflected by diffusion of I-131 radiolabeled albumin into the interstitial space, is comparable in liver and tumor before IHP but is significantly higher in tumor after IHP. The increased diffusion in the capillary tumor bed must occur through TNF-independent mechanisms such as intrinsic features of tumor neovasculature, hyperthermia, or other unrecognized perfusion-related factors. These data indicate that TNF must continue to be critically evaluated in clinical trials before it is routinely used with melphalan in isolated organ perfusion.
用肿瘤坏死因子（TNF）和美法仑对肝脏或肢体进行离体器官灌注，可使大多数患者的大块肿瘤消退。尽管数据表明TNF在这种情况下可能主要对肿瘤相关新血管发挥抗肿瘤作用，但其疗效尚不清楚。我们研究了在美法仑进行离体肝脏灌注（IHP）期间，TNF对肝脏和肿瘤组织中毛细血管渗漏的影响。27例局限于肝脏的不可切除癌症患者接受了60分钟的热IHP，单独使用1.5mg/kg美法仑（n = 7）或联合1.0mg TNF（n = 20）。使用术中渗漏监测I-131放射性标记白蛋白技术在所有患者中确认了完全的血管隔离。在IHP之前和之后立即采集肿瘤和肝脏样本。基线时肝脏与肿瘤中I-131放射性标记的每克组织计数（cpm）无差异（P2 = 0.44）。IHP后，肿瘤中的I-131白蛋白cpm高于肝脏（分别为10,999±1,976和3,821±780；P2 < 0.005）。然而，肿瘤中的I-131白蛋白cpm不受TNF影响（有TNF时为11,636±2,518，无TNF时为9,180±2,674；P2 = 0.59）。TNF不影响肿瘤中美法仑浓度（有TNF时为1,883±540 ng/g，无TNF时为1,854±861 ng/g；P2 = 0.9）。I-131放射性标记白蛋白扩散到间质空间所反映的毛细血管渗漏，在IHP之前肝脏和肿瘤中相当，但在IHP之后肿瘤中显著更高。肿瘤毛细血管床中扩散的增加必定通过与TNF无关的机制发生，如肿瘤新血管的固有特征、热疗或其他未被认识的灌注相关因素。这些数据表明，在TNF与美法仑在离体器官灌注中常规联合使用之前，必须在临床试验中继续对其进行严格评估。
