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

近年来，紫杉醇（TAX）联合卡铂（CBDCA）已被报道为晚期非小细胞肺癌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症，但已知TAX的组合降低了毒性。因此，我们在非小细胞肺癌患者中进行了CBDCA和TAX联合的I期研究，以确定它们的最大耐受剂量，并通过临床和分子药理学研究来研究血小板减少与血清血小板生成素（TPO）动力学的关系。CBDCA以6 mg×min/ml的目标曲线下面积（AUC）给药，并与每个队列递增剂量的TAX联合给药，从180 mg/m^2分4步递增至225 mg/m^2。采集用于CBDCA动力学和TPO动力学的血样。13例患者入组，发生了3级或4级治疗相关的白细胞减少症和中性粒细胞减少症，但是，剂量限制性 ...更多信息 未观察到毒性。在联合给药中未观察到TPO第8天/第1天与CBDCA单药给药时血小板最低值之间的负相关性。与CBDCA单独给药相比，联合给药后CBDCA的实际测量AUC和血小板减少率显著降低。本研究表明，TAX的推荐剂量为210 mg/m^2，CBDCA的目标AUC为6 mg×min/ml。此外，在组合中观察到血小板减少症的抑制作用。伴随该I期研究，收集血液样品并从外周单核细胞分离mRNA。在熊本大学用实时PCR系统定量外周血单个核细胞中CYP 3A 4和CYP 2C 8的基因表达。结果，TAX给药前后基因表达水平没有变化。这一结果表明，与多西他赛不同，TAX给药不会诱导其代谢酶Less

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