Naomoto Y, Tanaka N, Orita K
First Department of Surgery, Okayama University Medical School, Japan.
Acta Med Okayama. 1989 Aug;43(4):211-21. doi: 10.18926/AMO/30855.
We studied the in vivo antitumor effects of natural human tumor necrosis factor-alpha (nHuTNF-alpha) and natural human interferon-alpha (nHuIFN-alpha), both of which were produced by HVJ (hemagglutinating virus of Japan)-stimulated acute lymphatic B cell leukemia line, BALL-1 cells. To clarify the interaction between nHuTNF-alpha and nHuIFN-alpha, we used novel experimental models of lung metastasis and intraabdominal carcinomatosis which we developed in nude mice using a human tumor line, RPMI 4788. While the intravenous administration of nHuTNF-alpha or nHuIFN-alpha alone inhibited lung metastasis, the two cytokines given in combination synergistically inhibited lung metastasis. In a comparative study, nHuTNF-alpha and recombinant human interferon-gamma (rHuIFN-gamma) in combination also synergistically inhibited lung metastasis. Treatment with nHuTNF-alpha and nHuIFN-alpha combined significantly prolonged the survival of nude mice with intraabdominal carcinomatosis. Complete regression of five different human tumor xenografts was achieved by the simultaneous intratumoral injection of nHuTNF-alpha and nHuIFN-alpha. Histological examination revealed that tumor cell lysis occurred 24 h after the intratumoral administration of the cytokines. No significant signs of toxicity to nude mice were observed at any dose tested. The synergism of nHuTNF-alpha and nHuIFN-alpha may allow treatment at a relatively low dose range, thus minimizing side effects. The wide range of anticancer activity of these agents may provide better therapeutic efficacy. The in vivo assay systems which we have developed are useful for the analysis of the biological activities and interactions of cytokines and chemotherapeutic drugs.
我们研究了天然人肿瘤坏死因子-α（nHuTNF-α）和天然人干扰素-α（nHuIFN-α）的体内抗肿瘤作用，这两种因子均由经日本血凝病毒（HVJ）刺激的急性淋巴细胞B细胞白血病细胞系BALL-1细胞产生。为了阐明nHuTNF-α与nHuIFN-α之间的相互作用，我们使用了新型的肺转移和腹腔内癌形成实验模型，这些模型是我们利用人肿瘤细胞系RPMI 4788在裸鼠中建立的。单独静脉注射nHuTNF-α或nHuIFN-α可抑制肺转移，而联合给予这两种细胞因子则可协同抑制肺转移。在一项比较研究中，nHuTNF-α与重组人干扰素-γ（rHuIFN-γ）联合使用也可协同抑制肺转移。nHuTNF-α与nHuIFN-α联合治疗显著延长了患有腹腔内癌形成的裸鼠的生存期。通过同时瘤内注射nHuTNF-α和nHuIFN-α，实现了五种不同人肿瘤异种移植瘤的完全消退。组织学检查显示，在瘤内注射细胞因子24小时后发生了肿瘤细胞溶解。在任何测试剂量下均未观察到对裸鼠有明显的毒性迹象。nHuTNF-α与nHuIFN-α的协同作用可能允许在相对低剂量范围内进行治疗，从而将副作用降至最低。这些药物广泛的抗癌活性可能提供更好治疗效果。我们开发的体内检测系统对于分析细胞因子和化疗药物的生物活性及相互作用很有用。
