ACQUIRED TAMOXIFEN RESISTANCE - CORRELATION WITH REDUCED BREAST-TUMOR LEVELS OF TAMOXIFEN AND ISOMERIZATION OF TRANS-4-HYDROXYTAMOXIFEN
ACQUIRED TAMOXIFEN RESISTANCE - CORRELATION WITH REDUCED BREAST-TUMOR LEVELS OF TAMOXIFEN AND ISOMERIZATION OF TRANS-4-HYDROXYTAMOXIFEN
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DOI：
10.1093/jnci/83.20.1477
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发表时间：
1991-10-16
期刊：
影响因子：
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通讯作者：
DEGREGORIO, M
中科院分区：
文献类型：
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作者：
OSBORNE, CK;CORONADO, E;DEGREGORIO, M
获得性他莫昔芬耐药性是乳腺癌治疗失败的主要原因。 我们将雌激素受体阳性的 MCF-7 人乳腺癌细胞植入无胸腺裸 BALB/c 小鼠体内，作为模型研究体内获得性他莫昔芬耐药性。 通过反式他莫昔芬抑制肿瘤生长 4-6 个月后，尽管继续施用他莫昔芬，仍观察到肿瘤进展。 获得性耐药并不是由于雌激素受体的丧失、血清或肿瘤雌激素水平的变化、或血清中他莫昔芬或其主要代谢物的变化所致。 他莫昔芬耐药肿瘤在体内仍然依赖雌激素。 然而，耐药性也与他莫昔芬刺激肿瘤生长的能力有关。 耐药肿瘤的特点是细胞内他莫昔芬水平显着降低，以及有效的抗雌激素代谢物反式4-羟基他莫昔芬异构化为效力较低的顺式异构体。 因此，代谢耐受（通过他莫昔芬及其代谢物的细胞浓度的变化所体现）可能是乳腺癌获得性他莫昔芬耐药的一种机制。
Acquired tamoxifen resistance represents a major cause of treatment failure in breast cancer. We implanted estrogen receptor-positive MCF-7 human breast cancer cells in athymic nude BALB/c mice as a model to study in vivo acquired tamoxifen resistance. After 4-6 months of tumor growth suppression by trans-tamoxifen, tumor progression was observed despite continued tamoxifen administration. Acquired resistance was not due to loss of estrogen receptors, to alterations in serum or tumor estrogen levels, or to changes in tamoxifen or its major metabolites in serum. Tamoxifen-resistant tumors remained estrogen dependent in vivo. However, resistance was also associated with the ability of tamoxifen to stimulate tumor growth. Resistant tumors were characterized by markedly lower intracellular tamoxifen levels and by isomerization of the potent anti-estrogenic metabolite trans-4-hydroxytamoxifen to the less potent cis isomer. Metabolic tolerance, as manifested by alterations in cellular concentrations of tamoxifen and its metabolites, may thus be one mechanism for acquired tamoxifen resistance in breast cancer.