The prediction of adverse effect and determination of the maximum tolerated dose in chemotherapy of lung cancer based on clinical and molecular pharmacology

最近，紫杉醇(TAX)联合卡铂(CBDCA)已被报道为晚期非小细胞肺癌患者的标准化疗方案之一。虽然CBDCA的剂量限制性毒性是血小板减少，但已知联合使用TAX可降低其毒性。因此，我们对非小细胞肺癌患者进行了CBDCA和TAX联合治疗的I期研究，以确定它们的最大耐受量，并通过临床和分子药理学研究来探讨血小板减少症与血清血小板生成素(TPO)动力学的关系。CBDCA的曲线下靶区(AUC)为6 mg×min/m l，并结合4步递增的TAX剂量，从180 mg/m^2增加到225 mg/m^2。采集CBDCA动力学和TPO动力学的血样。13名患者入选，出现了3级或4级治疗相关的白细胞减少和中性粒细胞减少，然而，剂量限制的…没有观察到更多的毒性。联合用药时TPO第8天/第1天与单用CBDCA时的血小板最低值之间未见明显的负相关。与单独使用CBDCA相比，联合用药后CBDCA的实际测量AUC和血小板减少率均显著降低。结果表明，紫杉醇的推荐剂量为210 mg/m2，CBDCA靶向AUC为6 mg×min/ml，并观察到联合用药对血小板减少的抑制作用。在这项I期研究的同时，采集血样并从外周血单核细胞中分离出mRNA。用实时定量聚合酶链式反应系统定量检测熊本大学外周血单核细胞中细胞色素P3A4和细胞色素P42C8的基因表达。结果，在税收管理前后，基因表达水平没有变化。这一结果表明，与多西紫杉醇不同的是，给药不会减少其代谢酶的诱导。

Recently, the combination of paclitaxel (TAX) and carboplatin (CBDCA) has been reported one of the standard chemotherapies in patients with advanced non-small cell lung cancer. Although dose limiting toxicity of CBDCA is thrombocytopenia, it is known that the toxicity is decreased by the combination of TAX. Therefore, we conducted a phase I study of the combination with CBDCA and TAX in patients with non small cell lung cancer to determine the maximum-tolerated dose of them, and investigate the relationship between thrombocytopenia and serum thrombopoietin (TPO) kinetics by the clinical and molecular pharmacological studies. CBDCA was administered at a target area under the curve (AUC) of 6 mg×min/ml and in combination with escalating doses of TAX per cohort in 4 steps from 180 to 225 mg/m^2. Blood samples for CBDCA kinetics and TPO kinetics were collected. Thirteen patients were enrolled and grade 3 or 4 treatment-related leucocytopenia and neutropenia occurred, however, dose-limiting … More toxicity was not observed. The negative correlation between TPO day 8/day 1 and the nadir of thrombocytes which occurred at administration of CBDCA as a single agent, was not observed in the combination. The actual measured AUC of CBDCA and the rate of decreased thrombocytes diminished significantly in the combination compared with CBDCA alone. This study demonstrated that the recommended doses were 210 mg/m^2 of TAX, with CBDCA targeting AUC of 6 mg×min/ml. Moreover, the inhibitory effect of thrombocytopenia was observed in the combination. Accompanied with this phase I study, blood samples were collected and mRNA were isolated from peripheral mononuclear cells. The gene expressions of CYP3A4 and CYP2C8 in peripheral mononuclear cells were quantified with real-time PCR system at Kumamoto University. As a result, there was no change in levels of gene expressions before and after the administration of TAX. This result clarified that the administration of TAX unlike docetaxel did not induce its metabolic enzyme Less