Initial testing (stage 1) of the cyclin dependent kinase inhibitor SCH 727965 (dinaciclib) by the pediatric preclinical testing program.
Initial testing (stage 1) of the cyclin dependent kinase inhibitor SCH 727965 (dinaciclib) by the pediatric preclinical testing program.
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DOI：
10.1002/pbc.24073
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发表时间：
2012-12-15
影响因子：
3.2
通讯作者：
Smith MA
中科院分区：
文献类型：
--
作者：
Gorlick R;Kolb EA;Houghton PJ;Morton CL;Neale G;Keir ST;Carol H;Lock R;Phelps D;Kang MH;Reynolds CP;Maris JM;Billups C;Smith MA
SCH 727965是一种临床开发中的新药，可有效选择性抑制CDK 1、CDK 2、CDK 5和CDK 9。根据PPTP的体外和体内样本组评价SCH 727965的活性。在0.1 nM至1.0 μM浓度范围内，采用96小时暴露，检测SCH 727965对PPTP的体外组合。以40 mg/kg的剂量每周两次腹膜内给药2周，并在第21天重复，总观察期为6周，针对PPTP体内组进行测试。细胞系的中位IC 50值为7.5 nM，最小（3.4 nM）和最大（11.2 nM）IC 50值之间的范围小于4倍。SCH 727965对大多数细胞系的活性模式与细胞毒性一致。研究了43种异种移植模型，与对照组相比，SCH 727965在23/36例（64%）可评价实体瘤异种移植和3/7例ALL异种移植中诱导了无事件生存期分布的显著延迟。SCH 727965在实体瘤组中未诱导客观缓解，观察到的最佳缓解为1例骨肉瘤异种移植物的疾病稳定。在白血病组中，有两个客观缓解，在单个异种移植物中观察到完全缓解。SCH 727965显示了一种有趣的活性模式，表明其对选定的儿童癌症，特别是白血病的潜在适用性。
SCH 727965 is a novel drug in clinical development that potently and selectively inhibits CDK1, CDK2, CDK5, and CDK9. The activity of SCH 727965 was evaluated against the PPTP’s in vitro and in vivo panels. SCH 727965 was tested against the PPTP in vitro panel using 96 hour exposure at concentrations ranging from 0.1 nM to 1.0 μM. It was tested against the PPTP in vivo panels at a dose of 40 mg/kg administered intraperitoneally twice weekly for 2 weeks and repeated at Day 21 with a total observation period of 6 weeks. The median IC50 value for the cell lines was 7.5 nM, with less than 4-fold range between the minimum (3.4 nM) and maximum (11.2 nM) IC50 values. SCH 727965 demonstrated an activity pattern consistent with cytotoxicity for most of the cell lines. Forty-three xenograft models were studied and SCH 727965 induced significant delays in event free survival distribution compared to control in 23 of 36 (64%) evaluable solid tumor xenografts and in 3 of 7 ALL xenografts. SCH 727965 did not induce objective responses in the solid tumor panels and the best response observed was stable disease for one osteosarcoma xenograft. In the leukemia panel, there were two objective responses with a complete response observed in a single xenograft. SCH 727965 shows an interesting pattern of activity suggesting its potential applicability against selected childhood cancers, particularly leukemias.
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影响因子：
3.2
作者：
Houghton, Peter J.;Morton, Christopher L.;Smith, Malcolm A.
通讯作者：
Smith, Malcolm A.
影响因子：
45.3
作者：
Lin, Thomas S.;Ruppert, Amy S.;Byrd, John C.
通讯作者：
Byrd, John C.
DOI：
10.1097/coc.0b013e3181b2043f
发表时间：
2010-08-01
影响因子：
2.6
作者：
Fekrazad, Houman M.;Verschraegen, Claire F.;Rabinowitz, Ian
通讯作者：
Rabinowitz, Ian
影响因子：
1.5
作者：
Sebaugh, J. L.
通讯作者：
Sebaugh, J. L.
影响因子：
11.5
作者：
Bible, KC;Lensing, JL;Erlichman, C
通讯作者：
Erlichman, C