Kano Y, Akutsu M, Suzuki K, Yazawa Y, Tsunoda S, Furukawa Y
Division of Medical Oncology, Tochigi Cancer Center, Japan.
Oncol Res. 2000;12(3):137-48. doi: 10.3727/096504001108747611.
Raltitrexed (Tomudex) is a novel thymidylate synthase inhibitor with significant activity against advanced colorectal cancer. We studied the cytotoxic interactions of raltitrexed and 5-fluorouracil (5-FU) in four human colon cancer cell lines on various schedules. The cell growth inhibition after 5 days was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The cytotoxic interactions at the IC80 level were evaluated by the isobologram method. Simultaneous exposure to raltitrexed and 5-FU for 5 days produced additive to synergistic effects in Colo201 cells, and produced additive effects in Colo321, LoVo, and WiDr cells. Simultaneous exposure to raltitrexed and 5-FU for 24 h produced additive effects in Colo201, LoVo, and WiDr cells, and produced antagonistic effects in Colo320 cells. Sequential exposure to raltitrexed for 24 h followed by 5-FU for 24 h produced additive effects in Colo201, Colo320, and LoVo cells, and produced antagonistic effects in WiDr cells. The reverse sequence produced additive effects in Colo201 cells, and produced antagonistic effects in Colo320, LoVo, and WiDr cells. Simultaneous exposure to raltitrexed and 5-FU for 4 h and sequential exposure to raltitrexed for 4 h followed by 5-FU for 4 h with a 20-h interval produced additive effects, while the reverse sequence produced antagonistic effects in LoVo and WiDr cells. These findings suggest that the simultaneous administration of raltitrexed and 5-FU or the sequential administration of raltitrexed followed by 5-FU may be the optimal sequence, while the reverse sequence may be inappropriate. Preclinical and clinical studies of the simultaneous administration of raltitrexed and 5-FU and the sequential administration of raltitrexed followed by 5-FU are required to better understand the antitumor, toxic, and pharmacokinetic interactions of this combination in order to develop the combination chemotherapy of raltitrexed and 5-FU.
雷替曲塞（商品名：拓优得）是一种新型胸苷酸合成酶抑制剂，对晚期结直肠癌具有显著活性。我们研究了雷替曲塞与5-氟尿嘧啶（5-FU）在四种人结肠癌细胞系中按不同给药方案联合时的细胞毒性相互作用。使用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）法测定5天后的细胞生长抑制情况。通过等效线图法评估IC80水平下的细胞毒性相互作用。雷替曲塞与5-FU同时暴露5天，在Colo201细胞中产生相加至协同效应，在Colo321、LoVo和WiDr细胞中产生相加效应。雷替曲塞与5-FU同时暴露24小时，在Colo201、LoVo和WiDr细胞中产生相加效应，在Colo320细胞中产生拮抗效应。先给予雷替曲塞24小时，随后给予5-FU 24小时，在Colo201、Colo320和LoVo细胞中产生相加效应，在WiDr细胞中产生拮抗效应。相反的给药顺序在Colo201细胞中产生相加效应，在Colo320、LoVo和WiDr细胞中产生拮抗效应。雷替曲塞与5-FU同时暴露4小时，以及先给予雷替曲塞4小时，间隔20小时后再给予5-FU 4小时，均产生相加效应，而相反的给药顺序在LoVo和WiDr细胞中产生拮抗效应。这些发现表明，雷替曲塞与5-FU同时给药或雷替曲塞后序贯给予5-FU可能是最佳给药顺序，而相反的顺序可能不合适。需要对雷替曲塞与5-FU同时给药以及雷替曲塞后序贯给予5-FU进行临床前和临床研究，以更好地了解该联合用药的抗肿瘤、毒性和药代动力学相互作用，从而开发雷替曲塞与5-FU的联合化疗方案。
