ABT-888, an orallyactive poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models
ABT-888, an orallyactive poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models
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DOI：
10.1158/1078-0432.ccr-06-3039
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发表时间：
2007-05-01
影响因子：
11.5
通讯作者：
Frost, David J.
中科院分区：
文献类型：
--
作者：
Donawho, Cherrie K.;Luo, Yan;Frost, David J.
目的：目的：评价新型口服生物可利用聚（ADP-核糖）聚合酶（PARP）抑制剂ABT-888的临床前药代动力学和抗肿瘤疗效。在体内疗效进行了评估，在同系和异种移植模型与替莫唑胺，铂，环磷酰胺，电离radiation.Results：ABT-888是一个有效的抑制剂PARP-1和PARP-2的K（i）的5.2和2.9 nmol/L，分别。该化合物具有良好的口服生物利用度并穿过血脑屏障。ABT-888在B16 F10 s.c.鼠黑素瘤模型。在ABT-888剂量低至3.1 mg/kg/d时，PARP抑制显著增加替莫唑胺的疗效，在25 mg/kg/d时达到最大疗效。在9 L原位大鼠胶质瘤模型中，单独使用替莫唑胺显示出最小的疗效，而ABT-888与替莫唑胺联合使用时，显著减缓了肿瘤进展。在MX-1乳腺异种移植模型（BRCA 1缺失和BRCA 2突变）中，ABT-888增强顺铂、卡铂和环磷酰胺，导致已建立的肿瘤消退，而单独使用相当剂量的细胞毒性药物，仅表现出适度的肿瘤抑制。最后，ABT-888增强了HCT-116结肠癌模型中的辐射（2戈伊/天x 10）。在每个模型中，ABT-888没有显示单药activity.Conclusions：ABT-888是一种有效的PARP抑制剂，具有良好的口服生物利用度，可以穿过血脑屏障，并增强替莫唑胺，铂类，环磷酰胺和放射在同系和异种移植肿瘤模型。这种广谱的化学增强和放射增强作用使该化合物成为临床评价的有吸引力的候选物。
Purpose: To evaluate the preclinical pharmacokinetics and antitumor efficacy of a novel orally bioavailable poly (ADP-ribose) polymerase (PARP) inhibitor, ABT-888.Experimental Design: In vitro potency was determined in a PARP-1 and PARP-2 enzyme assay. In vivo efficacy was evaluated in syngeneic and xenograft models in combination with temozolomide, platinums, cyclophosphamide, and ionizing radiation.Results: ABT-888 is a potent inhibitor of both PARP-1 and PARP-2 with K(i)s of 5.2 and 2.9 nmol/L, respectively. The compound has good oral bioavailability and crosses the blood-brain barrier. ABT-888 strongly potentiated temozolomide in the B16F10 s.c. murine melanoma model. PARP inhibition dramatically increased the efficacy of temozolomide at ABT-888 doses as low as 3.1 mg/kg/d and a maximal efficacy achieved at 25 mg/kg/d. In the 9L orthotopic rat glioma model, temozolomide alone exhibited minimal efficacy, whereas ABT-888, when combined with temozolomide, significantly slowed tumor progression. In the MX-1 breast xenograft model (BRCA1 deletion and BRCA2 mutation), ABT-888 potentiated cisplatin, carboplatin, and cyclophosphamide, causing regression of established tumors, whereas with comparable doses of cytotoxic agents alone, only modest tumor inhibition was exhibited. Finally, ABT-888 potentiated radiation (2 Gy/d x 10) in an HCT-116 colon carcinoma model. In each model, ABT-888 did not display single-agent activity.Conclusions: ABT-888 is a potent inhibitor of PARP, has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. This broad spectrum of chemopotentiation and radiopotentiation makes this compound an attractive candidate for clinical evaluation.