Stam T C, Swaak A J, Kruit W H, Stoter G, Eggermont A M
University Hospital Rotterdam, Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands.
Eur J Clin Invest. 2000 Apr;30(4):336-43. doi: 10.1046/j.1365-2362.2000.00632.x.
Tumour necrosis factor-alpha (TNFalpha) has been found to be very effective in the isolated limb perfusion setting for advanced extremity tumours. In a phase I study of intrapleural administration of TNFalpha 5 patients were followed for inflammatory response patterns.
Malignant mesothelioma patients were treated with repeated intrapleural administration of 0. 1-0.2 mg recombinant TNFalpha. Samples of serum and pleural fluid were taken at different time-points before and after TNFalpha-administration. Levels of TNFalpha, interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP) and secretory phospholipase A2 (sPLA2) were measured using enzyme-linked immunosorbent assays (ELISAs). Alpha 1-acid glycoprotein (alpha1-AG) was measured by nephelometry.
In pleural fluid TNFalpha and IL-8 reached peak levels, up to 50-700 ng mL-1 and 6-60 ng mL-1, respectively, 24 h after administration of TNFalpha. IL-6 (peak levels up to 250 ng mL-1) and sPLA2 peaked after 48 h. A slower and less dramatic pattern was observed for the levels of CRP and alpha1-AG. In serum no detectable levels of TNFalpha and no IL-8 were observed, whereas serum levels of IL-6, sPLA2 and CRP showed a clear increase after intrapleural administration of TNFalpha. Cytokines and acute-phase proteins showed the same pattern during subsequent cycles even up to 12 cycles. Tumour regression was not observed.
In the setting of a phase I study of repetitive intrapleural administration of TNFalpha in mesothelioma patients, we studied the characteristics of the inflammatory response. Intrapleural administration was followed by a clear inflammatory response locoregionally. In spite of TNFalpha peak levels as high as 700 ng mL-1 systemic levels were never detectable. The secondary cytokine response led to very high intrapleural IL-6 and IL-8 levels. Systemically IL-8 levels were never detectable whereas high IL-6 levels were induced systemically initially, with a decreased response to each intrapleural TNFalpha administration over time. The acute-phase response in contrast remained remarkably constant throughout the course of repeated intrapleural administrations of TNFalpha. Intrapleural administration of TNFalpha is well tolerated but associated with inconsistent and rather moderate impact on production of pleural fluid. This can be achieved by other simpler and cheaper treatment, thus we see no justification for further studies.
已发现肿瘤坏死因子-α（TNFα）在晚期肢体肿瘤的隔离肢体灌注治疗中非常有效。在一项关于胸膜腔内给予TNFα的I期研究中，对5例患者的炎症反应模式进行了随访。
恶性间皮瘤患者接受重复胸膜腔内给予0.1 - 0.2 mg重组TNFα治疗。在给予TNFα之前和之后的不同时间点采集血清和胸水样本。使用酶联免疫吸附测定（ELISA）法测量TNFα、白细胞介素-6（IL-6）、白细胞介素-8（IL-8）、C反应蛋白（CRP）和分泌型磷脂酶A2（sPLA2）的水平。通过散射比浊法测量α1-酸性糖蛋白（α1-AG）。
在胸水中，TNFα和IL-8在给予TNFα后24小时达到峰值水平，分别高达50 - 700 ng/mL和6 - 60 ng/mL。IL-6（峰值水平高达250 ng/mL）和sPLA2在48小时后达到峰值。CRP和α1-AG的水平呈现出较缓慢且不那么显著的变化模式。在血清中未检测到TNFα水平，也未检测到IL-8，而胸膜腔内给予TNFα后血清中IL-6、sPLA2和CRP水平明显升高。在后续周期直至12个周期中，细胞因子和急性期蛋白呈现相同模式。未观察到肿瘤消退。
在一项关于间皮瘤患者重复胸膜腔内给予TNFα的I期研究中，我们研究了炎症反应的特征。胸膜腔内给药后局部出现明显的炎症反应。尽管TNFα峰值水平高达每毫升700纳克，但从未检测到全身水平。继发性细胞因子反应导致胸水中IL-6和IL-8水平非常高。全身从未检测到IL-8水平，而全身最初诱导出高IL-6水平，随着时间推移，对每次胸膜腔内给予TNFα的反应逐渐降低。相比之下，在重复胸膜腔内给予TNFα的整个过程中，急性期反应保持相当稳定。胸膜腔内给予TNFα耐受性良好，但对胸水产生的影响不一致且较为适中。这可以通过其他更简单且更便宜的治疗方法实现，因此我们认为没有理由进行进一步研究。
