Takahashi N, Fiers W, Brouckaert P
Laboratory of Molecular Biology, Flanders Interuniversity Institute for Biotechnology, Ghent, Belgium.
Int J Cancer. 1995 Dec 11;63(6):846-54. doi: 10.1002/ijc.2910630616.
Repetitive administration of low doses of tumor necrosis factor (TNF) results in a state of selective tolerance to some of its effects. We have demonstrated that tolerance does not impair the therapeutic efficacy of TNF against a syngeneic murine B16BL6 melanoma and allows a complete cure. Another study, performed with a distinct tumor model, came to apparently contradictory results. To clarify this, we investigated whether the outcome depended on the tumor type and on the inclusion of interferon-gamma (IFN gamma) in the treatment. Three syngeneic tumors of different histological origin, i.e., B16BL6 melanoma, Lewis lung carcinoma (LLC) and EL4 lymphoma, were compared in C57BL/6 mice. The anti-tumor efficacy of TNF against B16BL6 and EL4 was not impaired in tolerant mice, but the effect of TNF against LLC was slightly, though significantly, reduced. Inclusion of IFN gamma in the treatment regimen, however, abolished this difference and resulted in complete cure for all 3 tumor systems. As therapeutically optimal doses were lethal in normal mice, only tolerance allowed a long-term cure. We conclude that the influence of tolerance on the anti-tumor activity of TNF as a single agent depends on the tumor type; in combination therapy with IFN gamma, however, tolerance allowed us to dissociate lethal toxicity from anti-tumor activity, irrespective of the tumor type tested.
重复给予低剂量肿瘤坏死因子（TNF）会导致对其某些效应产生选择性耐受状态。我们已证明，耐受不会损害TNF对同基因小鼠B16BL6黑色素瘤的治疗效果，且能实现完全治愈。另一项针对不同肿瘤模型开展的研究得出了明显矛盾的结果。为阐明这一点，我们研究了结果是否取决于肿瘤类型以及治疗中是否包含干扰素-γ（IFNγ）。在C57BL/6小鼠中比较了三种不同组织学来源的同基因肿瘤，即B16BL6黑色素瘤、Lewis肺癌（LLC）和EL4淋巴瘤。在耐受小鼠中，TNF对B16BL6和EL4的抗肿瘤效果未受损害，但TNF对LLC的效果虽有显著降低但降低幅度较小。然而，在治疗方案中加入IFNγ消除了这种差异，并导致所有三种肿瘤系统均实现完全治愈。由于治疗最佳剂量对正常小鼠具有致死性，只有耐受能实现长期治愈。我们得出结论，耐受对TNF作为单一药物的抗肿瘤活性的影响取决于肿瘤类型；然而，在与IFNγ联合治疗时，无论所测试的肿瘤类型如何，耐受都使我们能够将致死毒性与抗肿瘤活性分离。
