Wakeling A E
Cancer Research Department, ZENECA Pharmaceuticals, Macclesfield, Cheshire, England.
J Steroid Biochem Mol Biol. 1993 Dec;47(1-6):107-14. doi: 10.1016/0960-0760(93)90063-3.
A substantial proportion of patients with breast cancer are treated with the antioestrogen tamoxifen. As with other endocrine therapies, clinical experience has shown that some tumours in which growth is initially attenuated by tamoxifen treatment become resistant to continued drug treatment and resume growth. The mechanisms underlying the development of tamoxifen resistance have yet to be described but represent an important focus of research with the aim of defining what other therapies might be effective following tamoxifen treatment. Secondly, an understanding of tamoxifen resistance might suggest means to develop more effective agents for primary treatment of the disease. The development of pure antioestrogens, for example ICI 164,384 and ICI 182,780, which differ pharmacologically from tamoxifen in being entirely free of oestrogen partial-agonist activity, together with cell and animal models of tamoxifen resistant human breast cancer, has revealed one mechanism which might be of considerable clinical significance. Pure antioestrogens were shown to inhibit the proliferation of a greater proportion of tumor cells than tamoxifen in vitro, a differential effect that was attributed to the oestrogenic activity of tamoxifen. Subsequently, cell culture studies have shown that breast cancer cell lines selected for resistance to tamoxifen can still remain sensitive to the growth inhibitory action of pure antioestrogens. Similarly, the growth of human breast tumours in nude mice, which is initially attenuated by tamoxifen but then resumes, can be inhibited by pure antioestrogens. Both types of experiment are consistent with the view that tamoxifen resistance in these model systems is due to the oestrogenic action of tamoxifen. Thus, it can be predicted that in some patients whose tumours recur during tamoxifen therapy, a further response to pure antioestrogen treatment might occur. Studies to examine this hypothesis are currently being undertaken with ICI 182,780. One mechanism which might account for the experimental observations is an intrinsic heterogeneity amongst breast tumour cells in their response to tamoxifen, i.e. that there are at least two different populations of cells; one population which responds to tamoxifen as an antioestrogen and one which "reads" tamoxifen as an oestrogen. The growth advantage thus conferred on the latter population would lead to its predominance. If this is what actually happens in a proportion of human tumours, it can be argued that primary treatment of the tumour with a pure antioestrogen, rather than tamoxifen, would be preferred since a more complete and longer-lasting response would be predicted. Recent comparative studies with human breast tumours grown in nude mice support these predictions.
相当一部分乳腺癌患者接受抗雌激素药物他莫昔芬治疗。与其他内分泌疗法一样，临床经验表明，一些肿瘤最初经他莫昔芬治疗生长受到抑制，但随后会对持续的药物治疗产生耐药性并恢复生长。他莫昔芬耐药性产生的机制尚不清楚，但这是研究的一个重要重点，目的是确定他莫昔芬治疗后其他哪些疗法可能有效。其次，了解他莫昔芬耐药性可能会为开发更有效的原发性疾病治疗药物提供思路。例如ICI 164,384和ICI 182,780等纯抗雌激素药物的研发，它们在药理学上与他莫昔芬不同，完全没有雌激素部分激动剂活性，同时还有他莫昔芬耐药的人乳腺癌细胞和动物模型，揭示了一种可能具有重要临床意义的机制。体外实验表明，纯抗雌激素药物比他莫昔芬能抑制更大比例的肿瘤细胞增殖，这种差异效应归因于他莫昔芬的雌激素活性。随后，细胞培养研究表明，对他莫昔芬产生耐药性的乳腺癌细胞系对纯抗雌激素药物的生长抑制作用仍可能敏感。同样，裸鼠体内人乳腺肿瘤的生长最初受他莫昔芬抑制，但随后恢复，而纯抗雌激素药物可以抑制其生长。这两类实验都支持以下观点：在这些模型系统中，他莫昔芬耐药是由于他莫昔芬的雌激素作用。因此，可以预测，在一些他莫昔芬治疗期间肿瘤复发的患者中，可能会对纯抗雌激素治疗产生进一步反应。目前正在用ICI 182,780进行研究以检验这一假设。一种可能解释实验观察结果的机制是乳腺肿瘤细胞对他莫昔芬的反应存在内在异质性，即至少存在两种不同的细胞群体；一种群体将他莫昔芬视为抗雌激素药物作出反应，另一种群体将他莫昔芬“解读”为雌激素。因此赋予后一种群体的生长优势将导致其占主导地位。如果这确实在一部分人类肿瘤中发生，那么可以认为用纯抗雌激素药物而非他莫昔芬对肿瘤进行原发性治疗会更可取，因为预计会有更完全和更持久的反应。最近对裸鼠体内生长的人乳腺肿瘤进行的比较研究支持了这些预测。
