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一种用于聚(ADP-核糖)聚合酶抑制剂临床试验的酶联免疫吸附聚(ADP-核糖)聚合酶生物标志物检测法。

An enzyme-linked immunosorbent poly(ADP-ribose) polymerase biomarker assay for clinical trials of PARP inhibitors.

作者信息

Liu Xuesong, Palma Joann, Kinders Robert, Shi Yan, Donawho Cherrie, Ellis Paul A, Rodriguez Luis E, Colon-Lopez Milagros, Saltarelli Mary, LeBlond David, Lin C Thomas, Frost David J, Luo Yan, Giranda Vincent L

机构信息

Cancer Research, GPRD, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA.

出版信息

Anal Biochem. 2008 Oct 15;381(2):240-7. doi: 10.1016/j.ab.2008.07.007. Epub 2008 Jul 16.

Abstract

Many established cancer therapies involve DNA-damaging chemotherapy or radiotherapy. The DNA repair capacity of the tumor represents a common mechanism used by cancer cells to survive DNA-damaging therapy. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that is activated by DNA damage and has critical roles in DNA repair. Inhibition of PARP potentiates the activity of DNA-damaging agents such as temozolomide, topoisomerase inhibitors and radiation in both in vitro and in vivo preclinical models. Recently, several PARP inhibitors have entered clinical trials either as single agents or in combination with DNA-damaging chemotherapy. Because PARP inhibitors are not cytotoxic, a biomarker assay is useful to guide the selection of an optimal biological dose. We set out to develop an assay that enables us to detect 50% PAR reduction in human tumors with 80% power in a single-plate assay while assuring no more than a 10% false-positive rate. We have developed and optimized an enzyme-linked immunosorbent assay (ELISA) to measure PARP activity that meets the above-mentioned criterion. This robust assay is able to detect PAR levels of 30-2000 pg/ml in both tumor and peripheral blood monocyte samples. In a B16F10 mouse syngeneic tumor model, PARP inhibitor ABT-888 potentiates the effect of temozolomide in suppressing tumor growth, and PARP activity is greatly reduced by ABT-888 at efficacious doses. In summary, the ELISA assay described here is suitable for biomarker studies in clinical trials of PARP inhibitors.

摘要

许多已确立的癌症治疗方法涉及DNA损伤化疗或放疗。肿瘤的DNA修复能力是癌细胞用于在DNA损伤治疗中存活的常见机制。聚(ADP - 核糖)聚合酶(PARP)是一种核酶,可被DNA损伤激活,并在DNA修复中起关键作用。在体外和体内临床前模型中,抑制PARP可增强DNA损伤剂如替莫唑胺、拓扑异构酶抑制剂和辐射的活性。最近,几种PARP抑制剂已作为单一药物或与DNA损伤化疗联合进入临床试验。由于PARP抑制剂无细胞毒性,生物标志物检测有助于指导最佳生物学剂量的选择。我们着手开发一种检测方法,使我们能够在单孔检测中以80%的功效检测人类肿瘤中PAR降低50%,同时确保假阳性率不超过10%。我们已经开发并优化了一种酶联免疫吸附测定(ELISA)来测量PARP活性,该方法符合上述标准。这种可靠的检测方法能够检测肿瘤和外周血单核细胞样本中30 - 2000 pg/ml的PAR水平。在B16F10小鼠同基因肿瘤模型中,PARP抑制剂ABT - 888增强了替莫唑胺抑制肿瘤生长的效果,并且在有效剂量下ABT - 888可大大降低PARP活性。总之,本文所述的ELISA检测方法适用于PARP抑制剂临床试验中的生物标志物研究。

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