O'Reilly T, Wartmann M, Maira S-M, Hattenberger M, Vaxelaire J, Muller M, Ferretti S, Buchdunger E, Altmann K-H, McSheehy P M J
Oncology Research, Novartis Institutes for BioMedical Research, Basel, Switzerland.
Cancer Chemother Pharmacol. 2005 Apr;55(4):307-317. doi: 10.1007/s00280-004-0913-z. Epub 2004 Oct 26.
The microtubule-stabilizing agent patupilone (epothilone B, EPO906) and the tyrosine kinase inhibitor imatinib (STI571, Glivec) which primarily inhibits Bcr-Abl, PDGF and c-Kit tyrosine kinase receptors, were combined in vivo to determine if any interaction would occur with respect to antitumour effect and tolerability using rat C6 glioma xenografted into nude mice.
Patupilone and imatinib were administered alone or in combination at suboptimal doses. Imatinib treatment (orally once daily) was initiated 4 days after s.c. injection of rat C6 glioma cells into athymic nude mice and patupilone administration (i.v. once per week) was started 3 or 4 days after imatinib treatment.
As a single agent, imatinib was inactive in the regimens selected (100 mg/kg: T/C 86% and 116%; 200 mg/kg: T/C 68% and 84%; two independent experiments), but well tolerated (gain in body weight and no mortalities). Patupilone weekly monotherapy demonstrated dose-dependent antitumour effects (1 mg/kg: T/C 67% and 70%; 2 mg/kg: T/C 32% and 63%; 4 mg/kg: T/C 3% and 46%). As expected, dose-dependent body weight losses occurred (final body weight changes at 1 mg/kg were -7% and -3%; at 2 mg/kg were -23% and -13%; and at 4 mg/kg were -33% and -15%). Combining 2 mg/kg patupilone and 200 mg/kg per day imatinib in one experiment produced a non-statistically significant trend for an improved antitumour effect over patupilone alone (combination, T/C 9%), while in the second experiment, enhancement was seen with the combination and reached statistical significance versus patupilone alone (combination, T/C 22%; P=0.008). Reduction of the imatinib dose to 100 mg/kg per day resulted in no enhancement of antitumour activity in combination with 2 mg/kg patupilone. Reduction of the patupilone dose to 1 mg/kg resulted in a reduced antitumour effect, and only a trend for synergy with either imatinib dose (combination, T/C 46% and 40%). Pooling the data from the two experiments confirmed a significant synergy for the combination of 2 mg/kg patupilone and 200 mg/kg per day imatinib (P=0.032), and a trend for synergy at the 1 mg/kg patupilone dose. Reduction in the imatinib dose to 100 mg/kg per day resulted only in additivity with either dose of patupilone. Body weight losses were dominated by the effect of patupilone, since no greater body weight loss was observed in the combination groups.
Combining patupilone with high-dose imatinib produced an increased antitumour effect without affecting the tolerability of treatment in a relatively chemoresistant rat C6 glioma model. Such results indicate that further evaluation is warranted, in particular to elucidate possible mechanisms of combined action.
将微管稳定剂帕妥珠利（埃博霉素B，EPO906）与主要抑制Bcr - Abl、血小板衍生生长因子（PDGF）和c - Kit酪氨酸激酶受体的酪氨酸激酶抑制剂伊马替尼（STI571，格列卫）在体内联合使用，以确定将大鼠C6胶质瘤接种到裸鼠体内后，在抗肿瘤作用和耐受性方面是否会发生相互作用。
帕妥珠利和伊马替尼以次优剂量单独或联合给药。在将大鼠C6胶质瘤细胞皮下注射到无胸腺裸鼠体内4天后开始伊马替尼治疗（每日口服一次），在伊马替尼治疗3或4天后开始帕妥珠利给药（每周静脉注射一次）。
作为单一药物，伊马替尼在所选方案中无活性（100 mg/kg：T/C为86%和116%；200 mg/kg：T/C为68%和84%；两个独立实验），但耐受性良好（体重增加且无死亡）。帕妥珠利每周单药治疗显示出剂量依赖性抗肿瘤作用（1 mg/kg：T/C为67%和70%；2 mg/kg：T/C为32%和63%；4 mg/kg：T/C为3%和46%）。如预期的那样，出现了剂量依赖性体重减轻（1 mg/kg时最终体重变化为-7%和-3%；2 mg/kg时为-23%和-13%；4 mg/kg时为-33%和-15%）。在一个实验中，将2 mg/kg帕妥珠利和200 mg/kg/天伊马替尼联合使用，与单独使用帕妥珠利相比，抗肿瘤作用有改善的趋势，但无统计学意义（联合用药，T/C为9%），而在第二个实验中，联合用药有增强作用，与单独使用帕妥珠利相比达到统计学意义（联合用药，T/C为22%；P = 0.008）。将伊马替尼剂量降至100 mg/kg/天，与2 mg/kg帕妥珠利联合使用时未增强抗肿瘤活性。将帕妥珠利剂量降至1 mg/kg导致抗肿瘤作用降低，与任一伊马替尼剂量联合时仅显示协同趋势（联合用药，T/C为46%和40%）。汇总两个实验的数据证实，2 mg/kg帕妥珠利和200 mg/kg/天伊马替尼联合使用有显著协同作用（P = 0.032），在1 mg/kg帕妥珠利剂量时有协同趋势。将伊马替尼剂量降至100 mg/kg/天，仅与任一剂量的帕妥珠利有相加作用。体重减轻主要由帕妥珠利的作用主导，因为联合用药组未观察到更大的体重减轻。
在相对化疗耐药的大鼠C6胶质瘤模型中，将帕妥珠利与高剂量伊马替尼联合使用可增强抗肿瘤作用，且不影响治疗耐受性。这些结果表明有必要进行进一步评估，特别是阐明联合作用的可能机制。
