Koester S K, Maenpaa J U, Wiebe V J, Baker W J, Wurz G T, Seymour R C, Koehler R E, DeGregorio M W
University of Texas Health Science Center, Cancer Therapy & Research Center, San Antonio 78284-7884.
Breast Cancer Res Treat. 1994;32(1):57-65. doi: 10.1007/BF00666206.
Flow cytometric analysis of DNA ploidy and S-phase fraction are well recognized prognostic indicators in breast cancer. The present paper deals with the widening of the applications of flow cytometry to monitoring the effectiveness of antiestrogen therapy, detecting clonal selection and emergence of drug resistance, and monitoring chemosensitizing properties of drugs. Antiestrogen activity can be studied by DNA flow cytometry to address clinical research problems such as patient-specific pharmacokinetics, dosing compliance, and acquired antiestrogen resistance. Patient plasma specimens containing various concentrations of triphenylethylenes can be monitored for drug-induced effects using cell cycle measurements and correlated to in vivo drug levels. DNA flow cytometry has also been instrumental in the study of the effects of prolonged low-dose (0.5 microM for > 100 days) tamoxifen treatment on human estrogen receptor negative MDA-MB-231 cells, where it was shown that tamoxifen may significantly alter cell cycle kinetics and tumorigenicity of these cells, selecting a new, more aggressive, and rapidly growing clone. Lastly, it has been shown that the chemosensitizing properties of another triphenylethylene antiestrogen, toremifene, on estrogen receptor negative, multidrug resistant MDA-MB-231-A1 human breast cancer cells can be studied using flow cytometric analysis. Toremifene (and its metabolites N-desmethyltoremifene and toremifene IV) are able to "resensitize" MDA-MB-231-A1 cells to vinblastine and doxorubicin, as reflected in a marked shift of cells to G2/M phase of the cell cycle. Flow cytometry is a widely available technique that might be applied clinically to monitor, at the cellular level, drug effects on tumors, including the modulators of drug resistance.
DNA倍体和S期细胞分数的流式细胞术分析是乳腺癌中公认的预后指标。本文论述了流式细胞术在监测抗雌激素治疗效果、检测克隆选择和耐药性出现以及监测药物的化学增敏特性等方面应用范围的扩大。抗雌激素活性可通过DNA流式细胞术进行研究，以解决诸如患者特异性药代动力学、给药依从性和获得性抗雌激素耐药性等临床研究问题。可利用细胞周期测量监测含有不同浓度三苯乙烯的患者血浆标本的药物诱导效应，并将其与体内药物水平相关联。DNA流式细胞术在研究长期低剂量（0.5微摩尔，持续100天以上）他莫昔芬治疗对人雌激素受体阴性的MDA-MB-231细胞的影响方面也发挥了作用，结果表明他莫昔芬可能会显著改变这些细胞的细胞周期动力学和致瘤性，从而选择出一个新的、更具侵袭性且生长迅速的克隆。最后，研究表明，可使用流式细胞术分析来研究另一种三苯乙烯类抗雌激素药物托瑞米芬对雌激素受体阴性、多药耐药的MDA-MB-231-A1人乳腺癌细胞的化学增敏特性。托瑞米芬（及其代谢产物N-去甲基托瑞米芬和托瑞米芬IV）能够使MDA-MB-231-A1细胞对长春碱和阿霉素“重新敏感”，这表现为细胞明显向细胞周期的G2/M期转变。流式细胞术是一种广泛可用的技术，可在临床应用，在细胞水平监测药物对肿瘤的作用，包括耐药调节剂。
