Morikawa K, Fan D, Denkins Y M, Levin B, Gutterman J U, Walker S M, Fidler I J
Department of Cell Biology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Cancer Res. 1989 Feb 15;49(4):799-805.
The purpose of these studies was to determine the possible mechanisms responsible for the therapeutic effects of systemic administration of 5-fluorouracil (FUra) and gamma-interferon on disseminated human colon cancer. We used several human carcinoma cell lines that were established from different surgical specimens. Some lines were selected in nude mice for increased metastatic potential, and one line was selected in vitro for resistance to human recombinant gamma-interferon (r-IFN-gamma). In initial in vitro studies, FUra was cytostatic against all the human cell lines but did not produce cytolysis in any of the lines tested. The two r-IFN-gamma were species specific for both antitumor and immunomodulatory effects. Human r-IFN-gamma produced cytostatic and cytolytic effects against sensitive human colon carcinoma cells but did not activate tumoricidal properties in mouse macrophages. In contrast, mouse r-IFN-gamma had no direct cytotoxic effects against any of the human colon carcinoma lines but did activate tumoricidal properties in mouse macrophages. Human colon carcinoma cells (sensitive or resistant to human r-IFN-gamma) were implanted into the spleens of nude mice. Three days later, we began treatments with FUra and human or mouse r-IFN-gamma. In all experiments, the combination of FUra with mouse r-IFN-gamma produced the best therapeutic effects against growth of the cells in the spleen and in the liver. Because the mouse r-IFN-gamma is devoid of direct antitumor effects (against human tumor cells) but is a potent macrophage activator, these results suggest that the antitumor effects were due to direct antitumor effects of FUra and to activation of host defense mechanisms by the r-IFN-gamma.
这些研究的目的是确定全身给予5-氟尿嘧啶（FUra）和γ-干扰素对播散性人类结肠癌治疗作用的可能机制。我们使用了从不同手术标本建立的几种人类癌细胞系。一些细胞系在裸鼠中经筛选具有更高的转移潜能，一个细胞系在体外经筛选对人重组γ-干扰素（r-IFN-γ）具有抗性。在最初的体外研究中，FUra对所有人类细胞系均有细胞生长抑制作用，但在所测试的任何细胞系中均未产生细胞溶解作用。两种r-IFN-γ在抗肿瘤和免疫调节作用方面均具有种属特异性。人r-IFN-γ对敏感的人类结肠癌细胞产生细胞生长抑制和细胞溶解作用，但未激活小鼠巨噬细胞的杀肿瘤特性。相反，小鼠r-IFN-γ对任何人类结肠癌细胞系均无直接细胞毒性作用，但能激活小鼠巨噬细胞的杀肿瘤特性。将人类结肠癌细胞（对人r-IFN-γ敏感或耐药）植入裸鼠脾脏。三天后，我们开始用FUra和人或小鼠r-IFN-γ进行治疗。在所有实验中，FUra与小鼠r-IFN-γ联合使用对脾脏和肝脏中的细胞生长产生了最佳治疗效果。由于小鼠r-IFN-γ缺乏直接抗肿瘤作用（针对人类肿瘤细胞），但却是一种有效的巨噬细胞激活剂，这些结果表明抗肿瘤作用归因于FUra的直接抗肿瘤作用以及r-IFN-γ对宿主防御机制的激活。
