Inagawa H, Oshima H, Soma G, Mizuno D
Biotechnology Research Center, Teikyo University, Kanagawa, Japan.
J Biol Response Mod. 1988 Dec;7(6):596-607.
Enough amounts of tumor necrosis factor (TNF) in mice serum for the therapy were observed by treatment with 100 units of recombinant human TNF-alpha (rHuTNF-alpha) followed by administration of OK-432 (a streptococcal preparation). Optimal time interval between rTNF and OK-432 to produce endogenous TNF was 3 h, and priming activity of rTNF persisted for at least 10 h. The same effect was observed using novel human recombinant TNF-SAM2 (rHuTNF-SAM2) developed by our group. Production of endogenous TNF using rTNF-alpha or rTNF-SAM2 as a priming reagent was almost equal among various mice strains. Induced TNF in mice serum was completely neutralized by anti-MuTNF antiserum, but not by anti-HuTNF monoclonal antibody. rMuTNF could also induce the priming state; however, the dose-response kinetics of the priming effect to produce endogenous TNF was different between rHuTNFs and rMuTNF-alpha, suggesting species specificity among rTNFs used. The therapeutic effect against Meth A and MH134 tumors in mice treated by rHuTNFs in combination with OK-432 was superior to that by single administration of either OK-432 or rHuTNFs or by successive administrations of OK-432. Especially, the antitumor effect against MH134 hepatoma was superior to that of any other treatment using known biological response modifiers so far experienced. These results suggest that such combination antitumor therapy as rTNF together with OK-432 should be applicable to cancer patients.
通过用100单位重组人肿瘤坏死因子-α（rHuTNF-α）处理，随后给予OK-432（一种链球菌制剂），在小鼠血清中观察到了足以用于治疗的肿瘤坏死因子（TNF）量。rTNF和OK-432之间产生内源性TNF的最佳时间间隔为3小时，rTNF的启动活性持续至少10小时。使用我们小组开发的新型人重组TNF-SAM2（rHuTNF-SAM2）也观察到了相同的效果。在各种小鼠品系中，使用rTNF-α或rTNF-SAM2作为启动试剂产生内源性TNF的情况几乎相同。小鼠血清中诱导的TNF被抗MuTNF抗血清完全中和，但不被抗HuTNF单克隆抗体中和。rMuTNF也能诱导启动状态；然而，rHuTNFs和rMuTNF-α之间产生内源性TNF的启动效应的剂量反应动力学不同，这表明所用rTNFs之间存在种属特异性。rHuTNFs与OK-432联合治疗小鼠Meth A和MH134肿瘤的疗效优于单独给予OK-432或rHuTNFs或连续给予OK-432的疗效。特别是，对MH134肝癌的抗肿瘤作用优于迄今为止使用已知生物反应调节剂的任何其他治疗方法。这些结果表明，rTNF与OK-432这样的联合抗肿瘤疗法应该适用于癌症患者。
