De Soto Joseph A, Bowen Donnell, Davis Jillian H, Southerland William M, Hawkins Morris
Department of Pharmacology, Howard University College of Medicine, Washington, DC 20059, USA.
Anticancer Res. 2002 Mar-Apr;22(2A):1007-9.
The selective estrogen receptor modulator (SERM) and an agent for the prevention of osteoporosis in postmenopausal women, raloxifene (Ral), decreased high-dose methotrexate (MTX) cytotoxicity in MCF-7 breast cancer cells. When Ral is given at least 24 hours prior to MTX, the resultant interaction is antagonistic. However, when breast cancer cells are exposed to Ral 24 hours after MTX, the interaction between Ral and MTX is not antagonistic. The proliferation of cells exposed to 10 microM Ral and 10 microM MTX alone or in combination with Ral 24 hours prior to MTX was in had the following order: MTX > Ral 24 hours prior to MTX > Ral. MTX administration 24 hours prior to Ral had the following inhibitory effects on the growth of cells: MTX 24 hours prior to Ral > or = MTX > Ral 24 hours prior to MTX > Ral > control (no drug exposure). To determine if the antagonistic interaction between Ral and MTX was a function of sequence and time, cells were exposed to Ral 24 hours and 36 hours prior to MTX exposure. The percentages of control rates were 43.48 +/- 3.90% and 54.43 +/- 2.93%, respectively, from a 24 hours and 36 hours exposure of Ral prior to MTX. The growth rates after 24 h and 36 h exposures to MTX alone were 30.30 +/- 0.61% and 33.11 +/- 2.27% of control rates, respectively. These studies suggest that: (a) the interactions between Ral and MTX are sequence-dependent; (b) Ral antagonizes the effect of MTX when Ral administration precedes MTX; and (c) Ral antagonism to MTX is a function of time.
选择性雌激素受体调节剂（SERM）雷洛昔芬（Ral）是一种用于预防绝经后女性骨质疏松症的药物，它可降低MCF-7乳腺癌细胞中高剂量甲氨蝶呤（MTX）的细胞毒性。当在MTX给药前至少24小时给予Ral时，产生的相互作用是拮抗的。然而，当乳腺癌细胞在MTX给药24小时后暴露于Ral时，Ral与MTX之间的相互作用不是拮抗的。单独暴露于10μM Ral和10μM MTX或在MTX给药前24小时与Ral联合暴露的细胞增殖情况如下：MTX＞MTX给药前24小时的Ral＞Ral。在Ral给药前24小时给予MTX对细胞生长有以下抑制作用：Ral给药前24小时的MTX≥MTX＞MTX给药前24小时的Ral＞Ral＞对照（无药物暴露）。为了确定Ral与MTX之间的拮抗相互作用是否是顺序和时间的函数，在MTX暴露前24小时和36小时将细胞暴露于Ral。在MTX暴露前分别24小时和36小时暴露于Ral的对照率百分比分别为43.48±3.90%和54.43±2.93%。单独暴露于MTX 24小时和36小时后的生长率分别为对照率的30.30±0.61%和33.11±2.27%。这些研究表明：（a）Ral与MTX之间的相互作用是顺序依赖性的；（b）当Ral给药先于MTX时，Ral拮抗MTX的作用；（c）Ral对MTX的拮抗作用是时间的函数。
