Fridborg H, Jonsson E, Nygren P, Larsson R
Division of Clinical Pharmacology, University Hospital, Uppsala, Sweden.
Eur J Cancer. 1999 Mar;35(3):424-32. doi: 10.1016/s0959-8049(98)00286-x.
The aim of this investigation was to evaluate the relationship between the disease-specific activity of cytotoxic drugs in the clinic and in fresh human tumour cells from patients, as detected by a non-clonogenic cytotoxicity assay. The activity of 18 different cytotoxic drugs in fresh human tumour cells ex vivo was analysed in up to 15 samples from each of 13 different diagnoses using the fluorometric microculture cytotoxicity assay (FMCA). For each drug and diagnosis, relative activity indices (RAIs) were calculated, defined as the fraction of samples within the diagnosis having a survival index (SI) less than the median SI for the drug in all tested samples. Clinical response rates for the drug in the same diagnoses were collected from published phase II trials and were compared with the RAIs using Spearman's rank correlation (Rho) and Pearson's correlation coefficient (R). Correlation coefficients could be calculated for 12 drugs. The coefficients varied between 0.02 and 0.92 (Rho) and between 0.07 and 0.91 (R), but for most drugs the correlation between RAI and clinical response rates was good, with Rho > 0.6 and R > 0.7. Weak correlations were observed for cyclophosphamide and vincristine (Rho = 0.32 and 0.16, respectively), which might be due to old clinical data, and for paclitaxel (Rho = 0.02), which perhaps could be explained by in vitro activity of the solvent, Cremophor EL. The 18 drugs were also categorised according to their suggested clinical use in solid or haematological tumours, and were then compared regarding the activity in solid compared with haematological tumours ex vivo, expressed as the ratio between the number of responders among solid and haematological tumours (S/H ratio). The mean ex vivo S/H ratios in the group of drugs registered for use in haematological tumours was only 0.09 and was significantly different (P = 0.05) from the mean S/H ratios for the drugs used in both haematological and solid tumours (0.31) and in solid tumours only (0.47). Furthermore, the FMCA could identify the 50% most and least sensitive diagnoses with respect to clinical phase II activity with 74% (78/106) correct classifications. The results indicate that the relative activity of cytotoxic drugs in different diagnoses may be detected by the FMCA. Thus, 'phase II trials ex vivo' using non-clonogenic cytotoxicity assays might be used to make clinical trials more effective by targeting trials to diagnoses in which a new agent is most likely to be active.
本研究的目的是通过一种非克隆细胞毒性试验，评估临床中细胞毒性药物的疾病特异性活性与患者新鲜人肿瘤细胞中的活性之间的关系。使用荧光微量培养细胞毒性试验（FMCA），对来自13种不同诊断的多达15个样本中的新鲜人肿瘤细胞进行了18种不同细胞毒性药物的体外活性分析。对于每种药物和诊断，计算相对活性指数（RAI），定义为诊断内样本中生存指数（SI）小于该药物在所有测试样本中SI中位数的样本比例。从已发表的II期试验中收集相同诊断中该药物的临床缓解率，并使用Spearman秩相关（Rho）和Pearson相关系数（R）将其与RAI进行比较。12种药物可以计算相关系数。系数在0.02至0.92（Rho）和0.07至0.91（R）之间变化，但对于大多数药物，RAI与临床缓解率之间的相关性良好，Rho>0.6且R>0.7。观察到环磷酰胺和长春新碱的相关性较弱（Rho分别为0.32和0.16），这可能是由于临床数据陈旧，以及紫杉醇（Rho = 0.02），这可能可以用溶剂聚氧乙烯蓖麻油（Cremophor EL）的体外活性来解释。这18种药物还根据其在实体瘤或血液系统肿瘤中的建议临床用途进行了分类，然后比较了它们在实体瘤与血液系统肿瘤中的体外活性，以实体瘤和血液系统肿瘤中反应者数量的比例（S/H比）表示。注册用于血液系统肿瘤的药物组的平均体外S/H比仅为0.09，与用于血液系统肿瘤和实体瘤（0.31）以及仅用于实体瘤（0.47）的药物的平均S/H比有显著差异（P = 0.05）。此外，FMCA可以识别出在临床II期活性方面最敏感和最不敏感的50%的诊断，正确分类率为74%（78/106）。结果表明，FMCA可以检测细胞毒性药物在不同诊断中的相对活性。因此，使用非克隆细胞毒性试验的“体外II期试验”可能有助于通过将试验针对新药物最可能有活性的诊断来使临床试验更有效。
