Chung Francisco, Wang Liang-Chuan S, Kestell Philip, Baguley Bruce C, Ching Lai-Ming
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
Cancer Chemother Pharmacol. 2004 May;53(5):377-83. doi: 10.1007/s00280-003-0753-2. Epub 2004 Jan 13.
There is considerable current interest in the use of thalidomide as a single agent or in combination with drugs such as cyclophosphamide in the treatment of multiple myeloma and other cancers. Our previous work has shown that thalidomide potentiates the antitumour activity of both cyclophosphamide and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) against murine Colon 38 tumours. In both of these cases, thalidomide extends the half-life (t(1/2)) of the other drug. We wished to determine whether cyclophosphamide and DMXAA altered the t(1/2) of thalidomide. Since both thalidomide and DMXAA modulate tumour necrosis factor (TNF), we also wished to determine the role of TNF in this interaction.
Mice with Colon 38 tumours were treated with cyclophosphamide (220 mg/kg) and/or thalidomide (20 mg/kg) or DMXAA (25 mg/kg) and thalidomide (100 mg/kg), combinations that have previously demonstrated synergistic activity. Plasma and tumour tissue drug concentrations were analysed by high-performance liquid chromatography. To determine the role of TNF, similar experiments were performed using mice defective in the TNF gene (TNF(-/-)) or the TNF receptor-1 gene (TNFR1(-/-)).
Coadministration of cyclophosphamide increased the thalidomide t(1/2) by 3.9- and 3.6-fold, respectively, in plasma and tumour tissue, with a corresponding increase in the concentration-time curve (AUC). The corresponding values following coadministration of DMXAA were 3.0- and 4.6-fold, respectively. Coadministration of cyclophosphamide had similar effects on thalidomide t(1/2) in C57Bl/6, TNF(-/-) and TNFR1(-/-) mice, while coadministration of DMXAA did not alter the t(1/2) or AUC in TNF(-/-) and TNFR1(-/-) mice.
Both cyclophosphamide and DMXAA have a pharmacokinetic interaction with thalidomide, increasing t(1/2) and AUC. TNF mediates the effect of DMXAA on thalidomide pharmacokinetics but not that of cyclophosphamide.
目前人们对使用沙利度胺单药或与环磷酰胺等药物联合用于治疗多发性骨髓瘤和其他癌症有着浓厚兴趣。我们之前的研究表明，沙利度胺可增强环磷酰胺和5,6 - 二甲基呫吨酮 - 4 - 乙酸（DMXAA）对小鼠结肠38肿瘤的抗肿瘤活性。在这两种情况下，沙利度胺均可延长另一种药物的半衰期（t(1/2)）。我们希望确定环磷酰胺和DMXAA是否会改变沙利度胺的t(1/2)。由于沙利度胺和DMXAA均能调节肿瘤坏死因子（TNF），我们还希望确定TNF在这种相互作用中的作用。
给患有结肠38肿瘤的小鼠注射环磷酰胺（220 mg/kg）和/或沙利度胺（20 mg/kg），或DMXAA（25 mg/kg）和沙利度胺（100 mg/kg），这些组合先前已证明具有协同活性。通过高效液相色谱法分析血浆和肿瘤组织中的药物浓度。为确定TNF的作用，使用TNF基因缺陷（TNF(-/-)）或TNF受体 - 1基因缺陷（TNFR1(-/-)）的小鼠进行了类似实验。
联合使用环磷酰胺时，沙利度胺在血浆和肿瘤组织中的t(1/2)分别增加了3.9倍和3.6倍，浓度 - 时间曲线（AUC）相应增加。联合使用DMXAA后的相应值分别为3.0倍和4.6倍。联合使用环磷酰胺对C57Bl/6、TNF(-/-)和TNFR1(-/-)小鼠的沙利度胺t(1/2)有类似影响，而联合使用DMXAA对TNF(-/-)和TNFR1(-/-)小鼠的t(1/2)或AUC没有影响。
环磷酰胺和DMXAA与沙利度胺均存在药代动力学相互作用，可增加t(1/2)和AUC。TNF介导了DMXAA对沙利度胺药代动力学的影响，但不介导环磷酰胺的影响。
