Brunstein Flavia, Hoving Saske, aan de Wiel-Ambagtsheer Gisela, de Bruijn Ernst A, Guetens Gunther, Eggermont Alexander M M, ten Hagen Timo L M
Department of Surgical Oncology, Erasmus MC, Laboratory of Experimental Surgical Oncology, Daniel den Hoed Cancer Centre, Room Ee 0175, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands.
Cancer Immunol Immunother. 2007 Apr;56(4):573-80. doi: 10.1007/s00262-006-0206-y. Epub 2006 Aug 1.
Histamine (Hi) combined to melphalan in a rat experimental model of isolated limb perfusion (ILP) for lower limb soft tissue sarcoma, resulted in overall response rates (OR) of 66%. Likewise, ILP with interleukin-2 (IL-2) resulted in OR of 67%, when combined to melphalan, in the same experimental model. In systemic immunotherapy, the combination of IL-2 and Hi has been used for solid tumor treatment based on immunomodulatory effects. In this study, we used our well-established ILP experimental model to evaluate whether the synergistic effect between the two drugs seen in the systemic setting, could further improve response rates in a loco-regional setting. Histological evaluation was done directly and 24 h after ILP. Melphalan uptake by tumor and muscle were measured. Hi and IL-2 together, combined to melphalan in the ILP led to OR of only 28%. Histology of tumors demonstrated partial loss of Hi-induced hemorrhagic effect when IL-2 was present. Melphalan accumulation in the tumor when both Hi and IL-2 were added (3.1-fold) was very similar to accumulation with Hi only (2.8-fold), or IL-2 only (3.5-fold) combined to melphalan. In vitro there was no synergy between the drugs. In conclusion there was a negative synergistic effect between IL-2 and Hi in the regional setting.
在大鼠下肢软组织肉瘤的离体肢体灌注（ILP）实验模型中，组胺（Hi）与美法仑联合使用，总体缓解率（OR）为66%。同样，在同一实验模型中，白细胞介素-2（IL-2）与美法仑联合进行ILP时，总体缓解率为67%。在全身免疫治疗中，基于免疫调节作用，IL-2和Hi的联合已用于实体瘤治疗。在本研究中，我们使用已建立的ILP实验模型来评估在全身治疗中观察到的两种药物之间的协同效应，是否能在局部区域治疗中进一步提高缓解率。在ILP后直接以及24小时后进行组织学评估。测量肿瘤和肌肉对美法仑的摄取。在ILP中，Hi和IL-2一起与美法仑联合使用时，总体缓解率仅为28%。当存在IL-2时，肿瘤组织学显示Hi诱导的出血效应部分丧失。当同时添加Hi和IL-2时，肿瘤中美法仑的蓄积（3.1倍）与仅添加Hi（2.8倍）或仅添加IL-2（3.5倍）与美法仑联合时的蓄积非常相似。在体外，这些药物之间没有协同作用。总之，在局部区域治疗中，IL-2和Hi之间存在负协同效应。
