Lejeune F, Liénard D, Eggermont A, Schraffordt Koops H, Rosenkaimer F, Gérain J, Klaase J, Kroon B, Vanderveken J, Schmitz P
Centre Pluridisciplinaire d'Oncologie, CHUV, Lausanne, Switzerland.
J Cell Biochem. 1994 Sep;56(1):52-61. doi: 10.1002/jcb.240560110.
Recombinant tumor necrosis factor-alpha (rTNF alpha) has potent antitumor activity in experimental studies on human tumor xenografts. However, in humans, the administration of rTNF alpha is hampered by severe systemic side-effects. The maximum tolerated dose ranges from 350 to 500 mg/m2, which is at least 10-fold less than the efficient dose in animals. Isolation perfusion of the limbs (ILP) allows the delivery of high dose rTNF alpha in a closed system with acceptable side-effects. A protocol with triple-drug regimen was based on the reported synergism of rTNF alpha with chemotherapy, with interferon-gamma, and with hyperthermia. In melanoma-in-transit metastases (stage IIIA or AB) we obtained a 91% complete response, compared with 52% after ILP with melphalan alone. Release of nanograms levels of TNF alpha in the systemic circulation was evident but control of this leakage and appropriate intensive care resulted in acceptable toxicity. Angiographic, immunohistological, and immunological studies suggest that the efficacy of this protocol is due to a dual targeting: rTNF alpha activates and electively lyses the tumor endothelial cells while melphalan is mainly cytotoxic to the tumor cells. ILP with rTNF alpha appears to be a useful model for studying the biochemotherapy of cancer in man.
重组肿瘤坏死因子-α（rTNFα）在人肿瘤异种移植的实验研究中具有强大的抗肿瘤活性。然而，在人类中，rTNFα的给药受到严重全身副作用的阻碍。最大耐受剂量范围为350至500mg/m²，这比动物中的有效剂量至少低10倍。肢体隔离灌注（ILP）允许在副作用可接受的封闭系统中递送高剂量的rTNFα。一种三联药物方案基于已报道的rTNFα与化疗、干扰素-γ以及热疗的协同作用。在黑色素瘤的移行转移（IIIA期或AB期）中，我们获得了91%的完全缓解率，而单独使用美法仑进行ILP后的完全缓解率为52%。全身循环中纳克水平的TNFα释放明显，但对这种渗漏的控制和适当的重症监护导致了可接受的毒性。血管造影、免疫组织学和免疫学研究表明，该方案的疗效归因于双重靶向：rTNFα激活并选择性地裂解肿瘤内皮细胞，而美法仑主要对肿瘤细胞具有细胞毒性。含rTNFα的ILP似乎是研究人类癌症生物化疗的有用模型。
