Kase S, Kubota T, Watanabe M, Furukawa T, Tanino H, Ishibiki K, Teramoto T, Kitajima M
Department of Surgery, School of Medicine, Keio University, Tokyo, Japan.
Anticancer Res. 1993 Mar-Apr;13(2):369-73.
The modulating effect of human fibroblast-derived interferon beta (IFN-beta) on the antitumor effect of 5-fluorouracil (5-FU) against human colon carcinoma cells in vitro and in vivo was investigated. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay was carried out in vitro using the cultured human colon cancer cell line C-1. IFN-beta at concentrations of 50, 500, 5,000 and 50,000 IU/ml was added to the cultured tumor cells with or without 5-FU at concentrations of 10, 50 and 500 micrograms/ml. The antitumor activity of 5-FU with or without IFN-beta was assessed using Co-4, a human colon carcinoma xenograft in nude mice, with reference to thymidylate synthetase inhibition. IFN-beta was administered subcutaneously daily for 14 days at doses of 6,000, 60,000 and 600,000 IU/mouse. The combined antitumor effect with 5-FU was evaluated by simultaneous intraperitoneal administration of 5-FU at doses of 10 and 20 mg/kg daily for 10 days. The antitumor activity of IFN-beta alone increased in a dose-dependent manner against Co-4 in nude mice, whereas its antitumor activity in vitro against C-1 was limited. The synergistic effect of 5-FU and IFN-beta was observed both in vitro and in vivo, and the in vivo synergism was obtained without any enhancement of thymidylate synthetase inhibition or side effects in terms of death rate and body weight loss. These results suggest that the mechanism of the combined effect of 5-FU and IFN-beta is not related to enhancement of thymidylate synthetase inhibition or the host immune system, since human fibroblastoid IFN-beta is species-specific to humans. The clinical usefulness of this combination method for the treatment of advanced colorectal carcinoma is expected.
研究了人成纤维细胞源性β干扰素（IFN-β）对5-氟尿嘧啶（5-FU）体外及体内抗人结肠癌细胞作用的调节效应。采用3-(4,5-二甲基-2-噻唑基)-2,5-二苯基-2H四氮唑溴盐（MTT）法，以培养的人结肠癌细胞系C-1进行体外实验。将浓度为50、500、5000和50000 IU/ml的IFN-β添加到含有或不含有浓度为10、50和500μg/ml 5-FU的培养肿瘤细胞中。参照胸苷酸合成酶抑制情况，以裸鼠人结肠癌异种移植瘤Co-4评估5-FU联合或不联合IFN-β的抗肿瘤活性。IFN-β以6000、60000和600000 IU/小鼠的剂量每日皮下给药14天。通过每日腹腔注射剂量为10和20 mg/kg的5-FU，连续10天，评估其与5-FU的联合抗肿瘤效应。单独使用IFN-β时，其对裸鼠Co-4的抗肿瘤活性呈剂量依赖性增加，而其体外对C-1的抗肿瘤活性有限。5-FU与IFN-β在体外和体内均观察到协同效应，且在体内协同作用中，胸苷酸合成酶抑制未增强，死亡率和体重减轻方面也无副作用。这些结果表明，5-FU与IFN-β联合作用的机制与胸苷酸合成酶抑制增强或宿主免疫系统无关，因为人成纤维细胞样IFN-β对人具有种属特异性。期望这种联合方法在晚期结直肠癌治疗中的临床应用价值。
