van Ijken M G, van Etten B, de Wilt J H, van Tiel S T, ten Hagen T L, Eggermont A M
Department of Surgical Oncology, University Hospital Rotterdam/Daniël den Hoed Cancer Center, Rotterdam, The Netherlands.
J Immunother. 2000 Jul-Aug;23(4):449-55. doi: 10.1097/00002371-200007000-00008.
Isolated hepatic perfusion (IHP) is an attractive approach to treating nonresectable liver tumors, because the effects of systemic chemotherapy are poor and its application is hampered by severe general toxicity. In clinical and experimental settings, the efficacy of isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNF alpha) in combination with melphalan to treat melanoma in transit and soft-tissue sarcoma has been well established. In an ILP model in rats, the authors previously observed synergistic anti-tumor effects of TNF and melphalan on BN 175 soft-tissue sarcoma extremity tumors. The aim of the current study was to determine whether similar synergy in anti-tumor effects could be achieved by treating experimental BN 175 soft-tissue sarcoma liver tumors by IHP using these agents. The authors found that IHP with TNF and melphalan resulted in a dramatic increase in regional concentrations of perfused agents with virtually no concomitant systemic leakage. Isolated hepatic perfusion with only carrier solution resulted in a significantly diminished growth rate of BN 175 liver tumors compared with the growth rate of tumors in nonperfused rats. Perfusion with melphalan alone resulted in minimal anti-tumor effects. Perfusion with only TNF had a slight growth-stimulatory effect on the BN 175 liver tumors, but no negative effects on tumor growth were observed. When TNF was added to melphalan, a dramatic anti-tumor effect was observed. Thus, as in the rat ILP setting, the anti-tumor effect is augmented when TNF is added to IHP with melphalan to treat BN 175 soft-tissue sarcoma tumor-bearing rats. Strikingly, the tumor response was potentiated at relatively low concentrations of TNF compared with concentrations that elicited synergy with melphalan in ILP.
孤立肝灌注（IHP）是一种治疗不可切除肝肿瘤的有吸引力的方法，因为全身化疗效果不佳且其应用受到严重全身毒性的限制。在临床和实验环境中，肿瘤坏死因子-α（TNF-α）联合美法仑进行孤立肢体灌注（ILP）治疗皮肤转移黑色素瘤和软组织肉瘤的疗效已得到充分证实。在大鼠的ILP模型中，作者之前观察到TNF和美法仑对BN 175软组织肉瘤肢体肿瘤具有协同抗肿瘤作用。本研究的目的是确定使用这些药物通过IHP治疗实验性BN 175软组织肉瘤肝肿瘤是否能实现类似的抗肿瘤协同作用。作者发现，TNF和美法仑的IHP导致灌注药物的局部浓度显著增加，而几乎没有伴随的全身渗漏。仅用载体溶液进行孤立肝灌注导致BN 175肝肿瘤的生长速度与未灌注大鼠的肿瘤生长速度相比显著降低。单独使用美法仑灌注产生的抗肿瘤作用最小。仅用TNF灌注对BN 175肝肿瘤有轻微的生长刺激作用，但未观察到对肿瘤生长的负面影响。当TNF添加到美法仑中时，观察到显著的抗肿瘤作用。因此，与大鼠ILP情况一样，当TNF添加到美法仑的IHP中以治疗携带BN 175软组织肉瘤肿瘤的大鼠时，抗肿瘤作用增强。令人惊讶的是，与在ILP中引发与美法仑协同作用的浓度相比，在相对较低浓度的TNF下肿瘤反应增强。
