Effect of oestrogen receptor status and time on the intra-tumoural accumulation of tamoxifen and N-desmethyltamoxifen following short-term therapy in human primary breast cancer
Effect of oestrogen receptor status and time on the intra-tumoural accumulation of tamoxifen and N-desmethyltamoxifen following short-term therapy in human primary breast cancer
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雌激素受体状态和时间对人原发性乳腺癌短期治疗后他莫昔芬和 N-去甲基他莫昔芬瘤内蓄积的影响
DOI：
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发表时间：
1993
影响因子：
3.8
通讯作者：
M. Dowsett
中科院分区：
文献类型：
--
作者：
S. Johnston;B. Haynes;N. Sacks;J. Mckinna;L. Griggs;M. Jarman;M. Baum;I. Smith;M. Dowsett
摘要虽然人类乳腺癌中雌激素受体 (ER) 的存在可能决定对他莫昔芬的生物反应，但 ER 状态在多大程度上控制肿瘤他莫昔芬的积累尚不清楚。我们研究了短期治疗后 36 例人类乳腺癌中他莫昔芬 (TAM) 及其主要代谢物 N-去甲基他莫昔芬 (DMT) 的肿瘤内分布。治疗2周后似乎达到稳态血清浓度，此后ER-ve和ER+ve肿瘤之间TAM的瘤内浓度没有观察到显着差异（分别为717.9±166.4ng/gm和518.6±109.4ng/gm）。在治疗少于 2 周的患者中，与 ER + ve 肿瘤相比，ER − ve 肿瘤中的瘤内 TAM 显着减少（分别为 120.9 ± 49.9 ng/gm 和 450.1 ± 75.3 ng/gm；p < 0.04）。仅对于 ER − ve 肿瘤，肿瘤 TAM 积累率与治疗持续时间相关（r = 0.72，p < 0.02），而对于 ER + ve 肿瘤，绝对 ER 值似乎与 TAM 积累微弱相关（r = 0.41；p < 0.05）。 TAM与DMT的瘤内比率反映了ER-ve肿瘤中的血清浓度，但在ER+ve肿瘤中观察到相对更多的TAM与DMT。观察到 TAM 和 DMT 相似的细胞内分布，尽管治疗 2 周后，与 ER + ve 肿瘤相比，ER - ve 细胞质中每种化合物的含量相对较少（18% vs 34%）。这些结果表明，ER 状态可能影响他莫昔芬及其代谢物的积累速率和细胞内分布，但不影响所达到的最终浓度。稳态后，ER + ve 和 ER − ve 肿瘤（并非所有肿瘤都预期对药物产生反应）的肿瘤内浓度达到血清浓度的 5-7 倍。因此，与最近关于获得性耐药的报道不同，对他莫昔芬的从头耐药不太可能代表肿瘤无法在肿瘤内达到足够的药物或其代谢物浓度。
SummaryWhile the presence of oestrogen receptors (ERs) in human breast cancer may determine the biological response to tamoxifen, the extent to which ER status governs tumour tamoxifen accumulation is unclear. We investigated the intra-tumoural disposition of tamoxifen (TAM) and its major metabolite N-desmethyltamoxifen (DMT) in 36 human breast carcinomas following short-term therapy. Steady-state serum concentrations appeared to be reached following 2 weeks therapy, after which no significant difference in the intratumoural concentrations of TAM between ER − ve and ER + ve tumours was observed (717.9 ± 166.4 ng/gm, and 518.6 ± 109.4 ng/gm, respectively). In patients treated for less than 2 weeks, there was significantly less intra-tumoural TAM in ER − ve compared with ER + ve tumours (120.9 ± 49.9 ng/gm and 450.1 ± 75.3 ng/gm, respectively; p < 0.04). The rate of tumour TAM accumulation correlated with duration of therapy only for ER − ve tumours (r = 0.72, p < 0.02), whereas for ER + ve tumours the absolute ER value appeared to be weakly associated with TAM accumulation (r = 0.41; p < 0.05). The intra-tumoural ratio of TAM to DMT reflected the serum concentrations in ER − ve tumours, but in ER + ve tumours relatively more TAM to DMT was observed. A similar intracellular distribution of both TAM and DMT was observed, although following 2 weeks therapy relatively less of each compound was found in the cytosol of ER − ve compared with ER + ve tumours (18% vs 34%). These results demonstrate that ER status may influence the rate of accumulation and intra-cellular distribution of tamoxifen and its metabolites, but not the final concentrations which are achieved. Following steady-state, both ER + ve and ER − ve tumours, not all of which would be expected to respond to the drug, achieve intra-tumoural concentrations 5–7 fold greater than serum. Unlike recent reports on acquired resistance, therefore,de novo resistance to tamoxifen is unlikely to represent an inability of the tumour to achieve adequate intra-tumoural concentrations of the drug or its metabolites.
受体重新思考：20 年的视角。
DOI：
10.1016/b978-0-12-571138-8.50006-8
发表时间：
1982
期刊：
Recent progress in hormone research
影响因子：
--
作者：
Jensen,EV;Greene,GL;Closs,LE;DeSombre,ER;Nadji,M
通讯作者：
Nadji,M
雌激素受体阳性和阴性人乳腺癌细胞系中抗雌激素结合位点的表征和定量。
影响因子：
11.2
作者：
Miller,MA;Katzenellenbogen,BS
通讯作者：
Katzenellenbogen,BS
DOI：
10.1261/rna.052365.115
发表时间：
2015-11
期刊：
RNA (New York, N.Y.)
影响因子：
--
作者：
Popow J;Alleaume AM;Curk T;Schwarzl T;Sauer S;Hentze MW
通讯作者：
Hentze MW