ANTAGONISM OF CHEMOTHERAPY-INDUCED CYTO-TOXICITY FOR HUMAN-BREAST CANCER-CELLS BY ANTIESTROGENS
ANTAGONISM OF CHEMOTHERAPY-INDUCED CYTO-TOXICITY FOR HUMAN-BREAST CANCER-CELLS BY ANTIESTROGENS
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DOI：
10.1200/jco.1989.7.6.710
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发表时间：
1989-06-01
影响因子：
45.3
通讯作者：
ARTEAGA, CL
中科院分区：
文献类型：
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作者：
OSBORNE, CK;KITTEN, L;ARTEAGA, CL
在之前的一项国家外科辅助乳肠计划(NSABP)辅助研究中，在与马法兰和氟尿嘧啶一起进行化疗的同时，添加抗雌激素他莫昔芬对存活患者亚群产生不利影响，表明存在拮抗药物相互作用。为了研究这种可能性，我们研究了他莫昔芬和其他抗雌激素与几种细胞毒药物在培养的人乳腺癌细胞系中的相互作用。临床相关浓度的他莫昔芬和马法兰在集落形成试验中单独使用时可降低雌激素受体(ER)阳性乳腺癌细胞的集落存活率。然而，用他莫昔芬预处理细胞，然后暴露于马法兰，导致了拮抗作用，与单独使用马法兰相比，联合治疗存活的菌落更多。其他几种三苯基乙烯类抗雌激素也有相同的效果。即使预先与他莫昔芬短暂孵育，也观察到对细胞增殖没有影响的拮抗作用，这表明拮抗作用不是由于他莫昔芬已知的细胞动力学效应。他莫昔芬甚至在ER阴性的乳腺癌细胞和培养的肝细胞中对抗马法兰的细胞毒性。当马法兰与药理浓度的雌二醇或醋酸甲羟孕酮联合使用时，存在相加的药物相互作用，但与地塞米松也有拮抗作用。他莫昔芬也能拮抗氟尿嘧啶的细胞毒性。然而，当抗雌激素与阿霉素或4-羟基环磷酰胺结合时，发生了相加的相互作用，后者是一种烷化剂，通过与马法兰不同的载体介导机制进入细胞。为避免潜在的临床对抗，应避免将他莫昔芬与马法兰和/或氟尿嘧啶联合使用。
In a prior National Surgical Adjuvant Breast and Bowel Project (NSABP) adjuvant study, the addition of the antiestrogen tamoxifen to chemotherapy with melphalan and fluorouracil adversely affected survival patient subsets, suggesting an antagonistic drug interaction. To investigate this possibility, we studied the interaction of tamoxifen and other antiestrogens with several cytotoxic drugs in cultured human breast cancer cell lines. Clinically relevant concentrations of tamoxifen and melphalan reduced colony survival of estrogen receptor (ER)-positive breast cancer cells when used alone in a colony-forming assay. However, pretreatment of cells with tamoxifen followed by exposure to melphalan resulted in antagonism, with more colonies surviving treatment with the combination than with melphalan alone. Identical effects were seen using several other triphenylethelene antiestrogens. An antagonistic interaction was observed even with a brief preincubation with tamoxifen that had no effect on cell proliferation, indicating that antagonism was not due to tamoxifen''s known cell kinetic effects. Tamoxifen even antagonized melphalan cytotoxicity in ER-negative breast cancer cells and in cultured liver cells. An additive drug interaction occurred when melphalan was combined with pharmacologic concentrations of estradiol or medroxyprogesterone acetate, but antagonism was also observed with dexamethasone. Tamoxifen also antagonized the cytotoxicity of fluorouracil in these cells. However, an additive interaction occurred when the antiestrogen was combined with doxorubicin or 4-hydroxycyclophosphamide, an alkylating agent that is transported into the cell by a different carrier-mediated mechanism than melphalan. To avoid potential antagonism in the clinic, combinations of tamoxifen with melphalan and/or fluorouracil should be avoided.