Initial testing (stage 1) of M6620 (formerly VX-970), a novel ATR inhibitor, alone and combined with cisplatin and melphalan, by the Pediatric Preclinical Testing Program.
Initial testing (stage 1) of M6620 (formerly VX-970), a novel ATR inhibitor, alone and combined with cisplatin and melphalan, by the Pediatric Preclinical Testing Program.
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DOI：
10.1002/pbc.26825
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发表时间：
2018-03
影响因子：
3.2
通讯作者：
Smith MA
中科院分区：
文献类型：
--
作者：
Kurmasheva RT;Kurmashev D;Reynolds CP;Kang M;Wu J;Houghton PJ;Smith MA
M6620 是一种新型 DNA 损伤修复酶 ATR 抑制剂，可分别增强顺铂和伊立替康在 NSCLC 和结肠癌异种移植物中的活性。 M6620 的浓度范围为 1.0 nM 至 10.0 μM，并以 75 nM 的浓度与顺铂或美法仑联合进行了体外测试。 M6620 单独针对 24 个实体瘤异种移植物以及与顺铂联合进行了测试。在第1天和第8天以5mg/kg的剂量腹腔内施用顺铂。顺铂给药后约 16 小时，第 2 天和第 9 天以 20 mg/m2 静脉注射 M6620。 M6620 的中位相对 IC50 (rIC50) 值为 0.19 μM（范围 0.03–1.38 μM）。 M6620 使顺铂和美法仑的平均 IC50 分别降低了 1.48 倍和 1.95 倍。 M6620 作为体内单一药物，在 24 个实体瘤异种移植物中的 5 个（21%）中诱导了 EFS 分布的显着差异，但没有诱导客观反应。与对照相比，顺铂作为单一药物在 24 个实体瘤异种移植物中的 18 个（75%）中引起了 EFS 分布的显着差异。观察到对顺铂的三种客观反应。与对照相比，M6620 和顺铂组合在 24 例中的 21 例 (88%) 中引起了 EFS 分布的显着差异，有四种客观反应。 M6620 对某些细胞系显示出顺铂和美法仑活性的适度增强。 M6620 显示出很少的单药活性，并且将 M6620 添加到顺铂中可显着延长跨多种组织学的少数测试异种移植物的事件发生时间。
M6620 is a novel inhibitor of the DNA damage repair enzyme ATR, and has potentiated the activity of cisplatin and irinotecan in NSCLC and colon cancer xenografts, respectively. M6620 was tested in vitro at concentrations ranging from 1.0 nM to 10.0 μM and at 75 nM in combination with cisplatin or melphalan. M6620 was tested against 24 solid tumor xenografts alone and in combination with cisplatin. Cisplatin was administered intraperitoneally on day 1 and 8 at a dose of 5 mg/kg. M6620 was administered intravenously on days 2 and 9 at 20 mg/m2 approximately 16 hours after cisplatin. The median relative IC50 (rIC50) value for M6620 was 0.19 μM, (range 0.03–1.38 μM). M6620 reduced the mean IC50 of cisplatin and melphalan by 1.48- and 1.95-fold, respectively. M6620 as a single agent in vivo induced significant differences in EFS distribution in 5 of 24 (21%) solid tumor xenografts, but induced no objective responses. Cisplatin as a single agent induced significant differences in EFS distribution compared to control in 18 of 24 (75%) solid tumor xenografts. Three objective responses were observed to cisplatin. The M6620 and cisplatin combination induced significant differences in EFS distribution compared to control in 21 of 24 (88%), with four objective responses. M6620 showed modest potentiation of cisplatin and melphalan activity for some cell lines. M6620 showed little single agent activity and the addition of M6620 to cisplatin significantly prolonged time to event for a minority of tested xenografts across several histologies.
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