Smith G K, Amyx H, Boytos C M, Duch D S, Ferone R, Wilson H R
Division of Cell Biology, Wellcome Research Labs, Burroughs Wellcome, Research Triangle Park, North Carolina 27709, USA.
Cancer Res. 1995 Dec 15;55(24):6117-25.
The purpose of this investigation was to determine whether antitumor selectivity of the third generation thymidylate synthase inhibitor 1843U89 could be enhanced by a combination of the drug with folic acid. The effects of folic acid on toxicity of 1843U89 to the dog and mouse and on antitumor efficacy of 1843U89 in the mouse were studied. These data were compared to the effect of folic acid on the in vitro cell culture antitumor activity of 1843U89. The sensitivity of eight cancer cell lines (three ovarian, one colon, one ileocecal, one epidermoid, one osteosarcoma, and one breast line) to 1843U89 was tested in vitro in the presence and absence of folic acid. Folic acid concentrations greater than 100 microM were required to decrease 1843U89 activity in seven of the cell lines. Only the activity in HCT-8, the ileocecal line, was reserved at folic acid concentrations below 100 microM. Oral folic acid given 30 min prior to an i.v. dose of 1843U89 increased the maximally tolerated dose and the lethal dose of 1843U89, both in dogs and in thymidine-depleted mice. In mice, oral folic acid produced little or no effect upon the antitumor efficacy of 1843U89 in two of three tumor cell lines in vivo. HCT-8, the line that was sensitive to folate reversal in vitro, was also sensitive in vivo. The results show that an oral dose of folic acid 30 min prior to i.v. 1843U89 can block mouse and dog intestinal toxicity without decreasing efficacy of 1843U89 in two of three human tumor lines in the nude mouse. Thus, the data reported here indicate that the antitumor selectivity of 1843U89 may be enhanced through a combination of 1843U89 with oral folic acid.
本研究的目的是确定第三代胸苷酸合成酶抑制剂1843U89与叶酸联合使用是否能增强其抗肿瘤选择性。研究了叶酸对1843U89对犬和小鼠毒性的影响以及对1843U89在小鼠体内抗肿瘤疗效的影响。将这些数据与叶酸对1843U89体外细胞培养抗肿瘤活性的影响进行了比较。在有和没有叶酸的情况下，体外测试了八种癌细胞系（三种卵巢癌细胞系、一种结肠癌细胞系、一种回盲部癌细胞系、一种表皮样癌细胞系、一种骨肉瘤细胞系和一种乳腺癌细胞系）对1843U89的敏感性。在七种细胞系中，需要大于100微摩尔的叶酸浓度才能降低1843U89的活性。只有回盲部癌细胞系HCT-8在叶酸浓度低于100微摩尔时活性被保留。在静脉注射1843U89前30分钟口服叶酸，增加了犬和胸腺嘧啶核苷缺乏小鼠中1843U89的最大耐受剂量和致死剂量。在小鼠体内，口服叶酸对三种肿瘤细胞系中的两种体内1843U89的抗肿瘤疗效几乎没有影响。体外对叶酸逆转敏感的HCT-8细胞系在体内也敏感。结果表明，在静脉注射1843U89前30分钟口服叶酸可阻断小鼠和犬的肠道毒性，而不降低1843U89在裸鼠体内三种人肿瘤细胞系中的两种的疗效。因此，本文报道的数据表明，1843U89与口服叶酸联合使用可能会增强其抗肿瘤选择性。
