Hug V, Thames H, Blumenschein G R, Spitzer G, Drewinko B
Cancer Res. 1984 Mar;44(3):923-8.
The use of normal bone marrow (granulocyte-macrophage colony-forming units) as a point of reference to normalize the in vitro activities of anticancer agents has been investigated. The cytotoxic effects of four substituted anthraquinone derivatives, and of vinblastine on myeloid progenitors of different donors were reproducible up to a cell kill of approximately 60%. Equitoxic in vitro concentrations for normal bone marrows did not correlate with in vivo pharmacokinetic concentrations of these drugs. Breast tumor progenitor cells of 46 specimens were more sensitive than were bone marrow progenitors to the anthraquinone derivatives in 26 to 39% of instances, ratios which are similar to the clinically observed response rates of patients with breast carcinoma to these agents. Tumors were either sensitive or resistant to all four drugs in 68% (10 tumors were more sensitive, and 21 tumors were less sensitive than normal bone marrow); but in 32% of instances there were differences in tumor sensitivity for the four drugs, and the assay could select one to three drugs for which the tumor sensitivity was greater than that of bone marrow. Correlations of in vitro sensitivity and of clinical response to single agent treatments were determined in 21 patients, and the concordance was 71%. The value of the assay in predicting clinical response ranked best for sensitivity determinations within the normalized dose ranges, when testing within three different dose ranges was compared in a group of six patients. The concordance was higher in the small (1 or 2 metastatic sites) than in the large (greater than or equal to 3 metastatic sites) tumors (85 versus 50%), indicating a confounding influence of tumor load on the ability of the assay to predict efficacy of treatment. A rule of thumb is proposed for altering the in vitro sensitivity test results for large tumors that improves the overall concordance to 90%.
已对使用正常骨髓（粒细胞 - 巨噬细胞集落形成单位）作为参照点来标准化抗癌药物的体外活性进行了研究。四种取代蒽醌衍生物以及长春碱对不同供体的髓系祖细胞的细胞毒性作用在细胞杀伤率约为60%之前是可重复的。正常骨髓的等毒性体外浓度与这些药物的体内药代动力学浓度不相关。在26%至39%的情况下，46个标本的乳腺肿瘤祖细胞比骨髓祖细胞对蒽醌衍生物更敏感，这些比率与临床上观察到的乳腺癌患者对这些药物的反应率相似。68%的肿瘤对所有四种药物要么敏感要么耐药（10个肿瘤比正常骨髓更敏感，21个肿瘤比正常骨髓更不敏感）；但在32%的情况下，肿瘤对这四种药物的敏感性存在差异，该检测方法可以选择一至三种肿瘤敏感性高于骨髓的药物。在21例患者中确定了体外敏感性与单药治疗临床反应的相关性，一致性为71%。当在一组6例患者中比较在三个不同剂量范围内进行测试时，该检测方法在预测临床反应方面的价值在标准化剂量范围内进行敏感性测定时排名最佳。小肿瘤（1个或2个转移部位）的一致性高于大肿瘤（大于或等于3个转移部位）（85%对50%），表明肿瘤负荷对检测方法预测治疗疗效的能力有混杂影响。针对大肿瘤提出了一个经验法则来改变体外敏感性测试结果，从而将总体一致性提高到90%。
