Schedule-dependent synergism and antagonism between raltitrexed ("Tomudex") and methotrexate in human colon cancer cell lines in vitro
Schedule-dependent synergism and antagonism between raltitrexed ("Tomudex") and methotrexate in human colon cancer cell lines in vitro
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DOI：
10.1111/j.1349-7006.2001.tb01050.x
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发表时间：
2001-01-01
期刊：
影响因子：
--
通讯作者：
Furukawa, Y
中科院分区：
文献类型：
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作者：
Kano, Y;Akutsu, M;Furukawa, Y
叶酸依赖的酶是肿瘤化疗的靶点，抑制二氢叶酸还原酶的甲氨蝶呤(MTX)被广泛用于实体瘤和血液病的治疗，雷替曲塞(Tomudex)抑制胸苷合成酶，是一种新型的抗癌药物，对结直肠癌和其他一些实体瘤具有活性。我们研究了雷替曲塞和甲氨蝶呤联合应用对4种人结肠癌细胞株Colo201、Colo320、LoVo和WiDR的最佳联合用药方案，这些细胞同时暴露于雷替曲塞和甲氨蝶呤24 h，或者依次作用于雷替曲塞和甲氨蝶呤24 h，反之亦然。用四甲基偶氮唑盐(3-(4，5-dimethylthiazol-2-yl)-2，5-diphenyltetrazolium)比色法测定5天后细胞生长抑制率，用等线图法(Steel and Peckham，1979)分析药物对细胞生长抑制率分别为80%和50%的药物组合的效应。雷替曲塞和甲氨蝶呤的细胞毒作用具有时程依赖性，雷替曲塞和甲氨蝶呤同时作用在Colo201、LoVo和WiDR细胞中表现为相加效应，在Colo320细胞中表现为拮抗作用，雷替曲塞和甲氨蝶呤依次作用于四种细胞系均产生相加效应。在连续暴露于MTX和雷替曲塞之后，在Colo201、LoVo和WiDR细胞中产生了协同效应，在Colo320细胞中产生了相加效应。这些结果表明，在体外协同作用的基础上，MTX和雷替曲塞的序贯给药产生的细胞毒性超过预期，可能是细胞水平上的最佳方案，需要进一步的体内和临床研究来确定毒性和测试序贯给药的抗肿瘤效果。
The folate-dependent enzymes are attractive targets for cancer chemotherapy, Methotrexate (MTX), which inhibits dihydrofolate reductase, has been widely used for the treatment of solid tumors and hematological cancers, Raltitrexed (" Tomudex"), which inhibits thymidylate synthase, is a novel anticancer agent active against colorectal cancer and some other solid tumors. We studied the optimal schedule of raltitrexed and MTX in combination against four human colon cancer cell lines Colo201, Colo320, LoVo, and WiDr, These cells were simultaneously exposed to raltitrexed and MTX for 24 h, or sequentially exposed to raltitrexed for 24 h followed by MTX for 24 h, or vice versa. Cell growth inhibition after 5 days was determined by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, The effects of drug combinations at the concentrations of drug that produced 80% and 50% cell growth inhibition (IC80 and IC50) were analyzed by the isobologram method (Steel and Peckham, 1979), Cytotoxic interactions between raltitrexed and MTX were schedule-dependent, The simultaneous exposure to raltitrexed and MTX showed additive effects in Colo201, LoVo and WiDr cells and antagonistic effects in Colo320 cells, The sequential exposure to raltitrexed followed by MTX produced additive effects in all four cell lines. The sequential exposure to MTX followed by raltitrexed produced synergistic effects in Colo201, LoVo and WiDr cells and additive effects in Colo320 cells. These findings suggest that the sequential administration of MTX followed by raltitrexed produces more than the expected cytotoxicity and may be the optimal schedule at the cellular level, Further in vivo and clinical studies will be necessary to determine the toxicity and to test the antitumor effects of sequential administration of MTX followed by raltitrexed proposed on the basis of the in vitro synergism.