测序topotecan克服拓扑异构酶I和II和依托泊苷+顺铂电阻:基于例第一阶段试验。
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恩河J, Musanti R,啤酒,史密斯,Locsin年代,鲁宾呃
测序topotecan克服拓扑异构酶I和II和依托泊苷+顺铂电阻:基于例第一阶段试验。
癌症研究杂志2003年7月,9 (7):2504 - 9。
- PubMed ID
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12855624 (在PubMed]
- 文摘
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用途:抗拓扑异构酶(上)1和2抑制剂治疗失败,可能是一个重要的原因,可能是相关的,在某种程度上,下调的具体目标。调查人员在我们实验室以前提到的下调目标,以及一个互惠的老年病的交替。因此,测序前抑制剂可能会提供一个意味着克服阻力的顶级I和II抑制剂。此外,点突变在顶我,赋予抵抗我抑制剂,与担保对顺铂的敏感性有关。实验设计:剂量升级第一阶段试验topotecan(剂量的0.75至1.0毫克/米(2)/天)在天1到3依托泊苷(70 - 80 mg / m(2) /天)、顺铂(20 - 25毫克/米(2)/天)在8到10天。药物的时间序列是基于前一阶段我喜树碱的药代动力学和药效学研究和依托泊苷和顶部的水平目标在外周血单核细胞。结果:15例(男性和女性8 7日)收到40课程在三个剂量水平的治疗。中位数年龄为56岁(范围、39 - 77),和性能状态中值为1(范围,0 - 2)。诊断包括:非小细胞肺癌(7),头部和颈部癌症(2),癌症的未知的主(2),和1卵巢癌、前列腺癌、胃癌、肾癌。1级(topotecan 1.0毫克/米(2)/天; etoposide 80 mg/m(2)/day; and cisplatin 25 mg/m(2)/day) produced severe and prolonged febrile neutropenia in the first patient treated, and the subsequent patients were then entered onto a reduced dose level (cohort 2: topotecan 0.75 mg/m(2)/day; etoposide 70 mg/m(2)/day; and cisplatin 20 mg/m(2)/day). Three of 6 patients on cohort 2 experienced grade IV neutropenia >5 days, and a decision was then made to add filgrastim at 5 micro g/kg rather than additionally reduce the dosages (cohort 3). Eight patients were then treated on cohort 3, and 1 of the 8 patients experienced a grade 4 neutropenia. Thus, cohort level three was considered the recommended dose for Phase II studies. Twelve of the 15 patients had disease assessable for response to therapy. Seven achieved stable disease for >/==" BORDER="0">2 months, whereas 5 showed continued progression of their disease. CONCLUSIONS: These data show that sequencing TOP 1 and 2 inhibitors is feasible, and topotecan 0.75 mg/m(2)/day days 1-3; etoposide 70 mg/m(2)/day days 8-10; and cisplatin 20 mg/m(2)/day days 8-10 with filgrastim at 5 micro g/kg is an appropriate dose and schedule to test the concept of modulating TOP levels by sequencing the administration of the respective TOP inhibitors.