Initial testing (stage 1) of the proteasome inhibitor bortezomib by the pediatric preclinical testing program
Initial testing (stage 1) of the proteasome inhibitor bortezomib by the pediatric preclinical testing program
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DOI：
10.1002/pbc.21214
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发表时间：
2008-01-01
影响因子：
3.2
通讯作者：
Smith, Malcolm A.
中科院分区：
文献类型：
--
作者：
Houghton, Peter J.;Morton, Christopher L.;Smith, Malcolm A.
背景。硼替佐米是一种蛋白酶体抑制剂，已被美国食品药品监督管理局批准用于治疗多发性骨髓瘤，并且已在儿童中完成了1期试验。本研究的目的是评估硼替佐米在儿童临床前测试项目（PPTP）的儿童癌症体外和体内临床前模型中的抗肿瘤活性。
方法。硼替佐米在体外以0.1纳摩尔至1.0微摩尔的浓度对PPTP细胞系进行测试，并在体内以1毫克/千克的剂量进行测试，计划持续6周。
结果。硼替佐米对PPTP的体外细胞系具有一致的活性，中位半数抑制浓度（IC50）为23纳摩尔，且剂量 - 反应曲线陡峭。四种急性淋巴细胞白血病（ALL）细胞系的IC50值明显低于体外细胞系中的其他细胞系。在体内，硼替佐米对所测试的实体肿瘤异种移植物的活性有限，其中一个细胞系在事件发生时间测量方面符合中等活性标准，其余细胞系在此测量中显示低活性。硼替佐米对ALL细胞系在体内显示出活性，在7个可评估的细胞系中诱导出2个完全缓解和2个部分缓解。
结论。以其在小鼠中的最大耐受剂量给药时，硼替佐米对PPTP的ALL体内细胞系中的选定细胞系显示出活性。需要进一步的研究来确定硼替佐米与标准药物联合治疗儿童ALL时的活性。
Background. Bortezomib is a proteasome inhibitor that has been approved by FDA for the treatment of multiple myeloma and that has completed phase 1 testing in children. The purpose of the current study was to evaluate the antitumor activity of bortezomib against the in vitro and in vivo childhood cancer preclinical models of the Pediatric Preclinical Testing Program (PPTP). Procedures. Bortezomib was tested against the PPTP in vitro panel at concentrations ranging from 0.1 nM to 1.0 mu M and was tested in vivo at a dose of 1 mg/kg for a planned duration of 6 weeks. Results. Bortezomib was uniformly active against the PPTP's in vitro panel, with a median IC50 of 23 nM and with a steep dose-response curve. The four acute lymphoblastic leukemia (ALL) cell lines had significantly lower IC50 values compared to the remaining lines of the in vitro panel. Limited in vivo activity was observed for bortezomib against the solid tumor xenografts tested, with one line meeting criteria for intermediate activity for the time to event measure and with the remaining lines showing low activity for this measure. Bortezomib demonstrated in vivo activity against the ALL panel, inducing two complete and two partial responses among seven evaluable lines. Conclusions. Administered at its MTD in mice, bortezomib demonstrated activity against selected lines of the PPTP's ALL in vivo panel. Further studies are indicated to determine the activity of bortezomib when combined with standard agents to treat childhood ALL.