Bogdahn U, Drenkard D, Lutz M, Apfel R, Behl C
Department of Neurology, Julius Maximilians University of Würzburg, Federal Republic of Germany.
J Cancer Res Clin Oncol. 1991;117 Suppl 4(Suppl 4):S157-63. doi: 10.1007/BF01613223.
Combination chemotherapy is widely employed in clinical oncology; however, there is no generally accepted model to evaluate individual tumour susceptibility to a given drug combination protocol. We therefore investigated the drug interaction of ifosfamide (4-hydroxyperoxy-ifosfamide) and ACNU in a recently developed in vitro model of paired sequential combination chemotherapy in primary and metastatic malignant brain tumours. A long-term standard [6,3-3H]-thymidine-incorporation assay, employing a liquid scintillation counting protocol, was selected to assess the drug sensitivity of human tumours. In vitro drug exposures were derived from correlating in vivo-(systemic and CNS) and in vitro-pharmacokinetic drug parameters. In combination experiments tumour cells were treated sequentially by two drugs in both sequences: drug exposures were calculated for 2 h with a 1-h drug-free interval in between. "Cut-off" concentrations (maximum in vitro exposure doses) were calculated as 1.74 microM (for primary CNS tumours: 0.58 microM) for ifosfamide and 5.4 microM (for primary CNS tumours: 1.33 microM) for ACNU. Dose/response relations were derived from isotope incorporation rates after cells had grown for approximately five population doubling times. Combination isoboles were plotted after drug doses had been transformed into "equieffective doses", enabling comparison of drug combination effects. In all three glioblastomas (with CNS exposure dose) an additive or supra-additive effect could be observed in either sequence (in one tumour a biphasic additive isobole was found for both sequences). Out of three bronchial carcinomas (small-cell type, brain metastases) in two non-identical sequences a supra-additive effect was observed in two tumours, with antagonistic effects in the third tumour. In all three malignant melanomas and in one renal carcinoma antagonistic effects were observed, whereas in a second renal carcinoma supra-additive effects were demonstrated for both sequences. We conclude that drug combination chemotherapy effects at the cellular level may be extremely heterogeneous.
联合化疗在临床肿瘤学中被广泛应用；然而，目前尚无普遍接受的模型来评估个体肿瘤对特定联合用药方案的敏感性。因此，我们在最近建立的原发性和转移性恶性脑肿瘤配对序贯联合化疗体外模型中，研究了异环磷酰胺（4-羟基过氧异环磷酰胺）与ACNU的药物相互作用。我们选择了一种采用液体闪烁计数方案的长期标准[6,3-3H]-胸苷掺入试验，以评估人类肿瘤的药物敏感性。体外药物暴露是根据体内（全身和中枢神经系统）和体外药代动力学药物参数的相关性得出的。在联合实验中，肿瘤细胞按两种顺序依次用两种药物处理：药物暴露计算为2小时，中间有1小时的无药间隔。异环磷酰胺的“截止”浓度（最大体外暴露剂量）计算为1.74微摩尔/升（原发性中枢神经系统肿瘤为0.58微摩尔/升），ACNU为5.4微摩尔/升（原发性中枢神经系统肿瘤为1.33微摩尔/升）。剂量/反应关系是在细胞生长约五个群体倍增时间后，根据同位素掺入率得出的。在将药物剂量转换为“等效剂量”后绘制联合等效应线，以便比较联合用药效果。在所有三个胶质母细胞瘤（有中枢神经系统暴露剂量）中，两种顺序中均可观察到相加或超相加效应（在一个肿瘤中，两种顺序均发现双相相加等效应线）。在三个支气管癌（小细胞型，脑转移）中，在两个不同顺序的两个肿瘤中观察到超相加效应，在第三个肿瘤中观察到拮抗效应。在所有三个恶性黑色素瘤和一个肾癌中观察到拮抗效应，而在第二个肾癌中，两种顺序均显示超相加效应。我们得出结论，细胞水平的联合化疗效果可能极其异质。
