Bennett A, Gaffen J D, Melhuish P B, Stamford I F
Br J Pharmacol. 1987 May;91(1):229-35. doi: 10.1111/j.1476-5381.1987.tb09003.x.
The effect of indomethacin on the response of the NC carcinoma to methotrexate has been examined in vivo and in vitro. Survival was prolonged in mice treated with indomethacin 1.25 mg kg-1 twice daily plus methotrexate 4 mg kg-1 daily, compared to mice given either drug alone or controls. Indomethacin 1 microgram ml-1 increased the killing of cultured NC cells by methotrexate. This was not due to displacement of methotrexate from binding sites on the serum proteins. Nor was it due (entirely) to inhibition of prostaglandin synthesis, since flurbiprofen did not mimic the effect. Inhibition of cyclic AMP phosphodiesterase seems unlikely to explain the effect of indomethacin since theophylline had little or no effect on NC cell killing by methotrexate. Indomethacin 1 microgram ml-1 increased the accumulation of tritium in NC cells incubated with [3H]-methotrexate. In contrast, with normal epithelial cells from human embryonic intestine, indomethacin 1 microgram ml-1 did not alter the cytotoxicity of methotrexate or the accumulation of tritium during incubation with [3H]-methotrexate. The beneficial interaction between indomethacin and methotrexate may have therapeutic potential in man.
已在体内和体外研究了吲哚美辛对NC癌对甲氨蝶呤反应的影响。与单独给予任一药物或作为对照的小鼠相比，每天两次给予1.25 mg/kg吲哚美辛加每天给予4 mg/kg甲氨蝶呤的小鼠生存期延长。1微克/毫升的吲哚美辛增加了甲氨蝶呤对培养的NC细胞的杀伤作用。这不是由于甲氨蝶呤从血清蛋白结合位点上被置换所致。也不是（完全）由于前列腺素合成受到抑制，因为氟比洛芬不能模拟这种作用。环磷酸腺苷磷酸二酯酶的抑制似乎不太可能解释吲哚美辛的作用，因为茶碱对甲氨蝶呤杀伤NC细胞几乎没有影响。1微克/毫升的吲哚美辛增加了用[3H] - 甲氨蝶呤孵育的NC细胞中氚的积累。相比之下，对于来自人胚胎肠道的正常上皮细胞，1微克/毫升的吲哚美辛在与[3H] - 甲氨蝶呤孵育期间并未改变甲氨蝶呤的细胞毒性或氚的积累。吲哚美辛与甲氨蝶呤之间的有益相互作用可能对人类具有治疗潜力。
