Aquino A, Prete S P, Greiner J W, Giuliani A, Graziani G, Turriziani M, De Filippi R, Masci G, Bonmassar E, De Vecchis L
Department of Neuroscience, University of Rome, Tor Vergata, Italy.
Clin Cancer Res. 1998 Oct;4(10):2473-81.
5-Fluorouracil (5-FU) and human recombinant gamma-interferon (gamma-IFN) were found to increase the expression of carcinoembryonic antigen (CEA) in human cancer cells in vitro. In the present study, the antimetabolite was associated with gamma-IFN or folinic acid (FA), a biochemical modulator of cellular metabolism of 5-FU, able to increase its antineoplastic activity. Treatment of two human colon cancer cell lines (HT-29 and WiDr) with 5-FU + gamma-IFN resulted in an increase of CEA expression higher than that obtainable with both agents alone, although no synergistic effects were obtained. This was demonstrated in terms of: (a) mRNA transcripts (HT-29); (b) cytoplasm and membrane CEA protein levels detected by Western blot analysis (HT-29); and (c) plasma membrane reactivity determined by flow cytometry analysis (HT-29 and WiDr). Moreover, 5-FU + gamma-IFN increased HLA class I molecules in the HT-29 cell membrane over that obtainable with gamma-IFN alone. In contrast, both agents did not induce the expression of the costimulatory molecule B7-1. Treatment with FA enhanced the antitumor effect of 5-FU but not its ability to augment CEA expression. This suggests that the FA-sensitive biochemical mechanism of action of 5-FU is not involved in its effect on CEA expression. In vivo studies showed, for the first time, that 5-FU, alone or combined with gamma-IFN, increases the amount of CEA protein over controls, either in cancer cells or in peripheral blood of nude mice bearing HT-29 cells. These results could be of potential diagnostic and/or therapeutic value when CEA protein is the target of humoral or cell-mediated immunity.
5-氟尿嘧啶（5-FU）和人重组γ-干扰素（γ-IFN）在体外可增加人癌细胞中癌胚抗原（CEA）的表达。在本研究中，这种抗代谢物与γ-IFN或亚叶酸（FA）联合使用，FA是5-FU细胞代谢的生化调节剂，能够增强其抗肿瘤活性。用5-FU +γ-IFN处理两种人结肠癌细胞系（HT-29和WiDr）后，CEA表达的增加高于单独使用这两种药物时的增加幅度，尽管未获得协同效应。这在以下方面得到了证实：（a）mRNA转录本（HT-29）；（b）通过蛋白质印迹分析检测到的细胞质和膜CEA蛋白水平（HT-29）；以及（c）通过流式细胞术分析测定的质膜反应性（HT-29和WiDr）。此外，5-FU +γ-IFN使HT-29细胞膜中的HLA I类分子比单独使用γ-IFN时有所增加。相比之下，这两种药物均未诱导共刺激分子B7-1的表达。用FA处理可增强5-FU的抗肿瘤作用，但不增强其增加CEA表达的能力。这表明5-FU对FA敏感的生化作用机制与其对CEA表达的影响无关。体内研究首次表明，5-FU单独或与γ-IFN联合使用，可使携带HT-29细胞的裸鼠癌细胞或外周血中的CEA蛋白量相对于对照组增加。当CEA蛋白是体液免疫或细胞介导免疫靶点时，这些结果可能具有潜在的诊断和/或治疗价值。
