Talmadge J E, Tribble H R, Pennington R W, Phillips H, Wiltrout R H
Cancer Res. 1987 May 15;47(10):2563-70.
These studies were designed to examine the immunodulatory and immunotherapeutic properties of recombinant murine interferon gamma (rM IFN-gamma) and recombinant human tumor necrosis factor (rH TNF). We report that rM IFN-gamma activated murine natural killer cells and macrophages in a dose-dependent manner in vivo. The rM IFN-gamma, which demonstrated a bell-shaped therapeutic response curve, must be administered at specific doses and schedules to produce optimal therapeutic activity. Optimal activity was observed after i.v. administration of 50,000 U/animal rM IFN-gamma three times per week. In contrast, rH TNF produced its major therapeutic activity in the treatment of metastatic disease after i.v. but not i.p. administration. The therapeutic effects of rH TNF were as great in these in vivo systems as those of rM IFN-gamma. Furthermore, rH TNF had additive therapeutic activity when administered in conjunction with suboptimal doses of rM IFN-gamma. Unlike rM IFN-gamma, rH TNF did not activate natural killer cells in vivo or in vitro but did augment in vivo and in vitro macrophage tumoricidal activity. It also had synergistic cytostatic properties with rM IFN-gamma for some murine tumor cell lines in vitro. High levels of rH TNF were readily detected in the serum with a half-life of approximately 30 min after i.v. administration. In contrast, only minimal serum TNF activity occurred after i.p. administration, suggesting that i.v. administration may more efficiently facilitate systemic therapeutic activity. In summary, rH TNF and rM IFN-gamma have therapeutic activity for metastatic disease as individual agents and additive therapeutic activity when used in combination. Furthermore, it appears that in addition to therapeutic potential as cytostatic agents, the immunomodulatory properties of rH TNF have a role in its therapeutic properties.
这些研究旨在检验重组鼠干扰素γ（rM IFN-γ）和重组人肿瘤坏死因子（rH TNF）的免疫调节及免疫治疗特性。我们报告，rM IFN-γ在体内以剂量依赖方式激活鼠自然杀伤细胞和巨噬细胞。呈钟形治疗反应曲线的rM IFN-γ，必须按特定剂量和给药方案给药才能产生最佳治疗活性。静脉注射50,000 U/只动物的rM IFN-γ，每周3次，可观察到最佳活性。相比之下，rH TNF在静脉注射而非腹腔注射后，对转移性疾病治疗产生主要治疗活性。在这些体内系统中，rH TNF的治疗效果与rM IFN-γ的治疗效果一样显著。此外，rH TNF与次优剂量的rM IFN-γ联合给药时具有相加治疗活性。与rM IFN-γ不同，rH TNF在体内和体外均未激活自然杀伤细胞，但确实增强了体内和体外巨噬细胞的杀肿瘤活性。在体外，它对某些鼠肿瘤细胞系与rM IFN-γ也具有协同细胞生长抑制特性。静脉注射后，血清中很容易检测到高水平的rH TNF，其半衰期约为30分钟。相比之下，腹腔注射后仅出现最低限度的血清TNF活性，这表明静脉注射可能更有效地促进全身治疗活性。总之，rH TNF和rM IFN-γ作为单一药物对转移性疾病具有治疗活性，联合使用时具有相加治疗活性。此外，似乎rH TNF除了具有作为细胞生长抑制剂的治疗潜力外，其免疫调节特性在其治疗特性中也发挥作用。
