Houghton Peter J, Morton Christopher L, Kolb E Anders, Lock Richard, Carol Hernan, Reynolds C Patrick, Keshelava Nino, Maris John M, Keir Stephen T, Wu Jianrong, Smith Malcolm A
St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Pediatr Blood Cancer. 2008 Jan;50(1):37-45. doi: 10.1002/pbc.21214.
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).
Bortezomib was tested against the PPTP in vitro panel at concentrations ranging from 0.1 nM to 1.0 microM and was tested in vivo at a dose of 1 mg/kg for a planned duration of 6 weeks.
Bortezomib was uniformly active against the PPTP's in vitro panel, with a median IC(50) of 23 nM and with a steep dose-response curve. The four acute lymphoblastic leukemia (ALL) cell lines had significantly lower IC(50) 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.
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.
硼替佐米是一种蛋白酶体抑制剂，已获美国食品药品监督管理局（FDA）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对儿科临床前测试项目（PPTP）的体外和体内儿童癌症临床前模型的抗肿瘤活性。
硼替佐米在体外以0.1 nM至1.0 microM的浓度对PPTP进行测试，并在体内以1 mg/kg的剂量进行测试，计划持续6周。
硼替佐米对PPTP的体外测试组均具有活性，中位半数抑制浓度（IC50）为23 nM，且剂量反应曲线较陡。与体外测试组的其他细胞系相比，四种急性淋巴细胞白血病（ALL）细胞系的IC50值显著更低。观察到硼替佐米对所测试的实体瘤异种移植的体内活性有限，其中一个细胞系在事件发生时间测量方面符合中度活性标准，其余细胞系在此测量中显示低活性。硼替佐米在体内对ALL测试组显示出活性，在七个可评估的细胞系中诱导了两个完全缓解和两个部分缓解。
在小鼠中以最大耐受剂量给药时，硼替佐米对PPTP体内ALL测试组的选定细胞系显示出活性。需要进一步研究以确定硼替佐米与标准药物联合治疗儿童ALL时的活性。
