Whitacre C M, Zborowska E, Willson J K, Berger N A
Department of Medicine and Cancer Center, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106-4937, USA.
Clin Cancer Res. 1999 Mar;5(3):665-72.
Cleavage of poly(ADP-ribose) polymerase (PARP) by caspases is a prominent characteristic of apoptosis or programmed cell death shown to be induced by topoisomerase (Topo) inhibitors. Because Topo I inhibitors have been shown to be effective in the treatment of some patients with colon cancer, we considered the possibility of using PARP cleavage as an early predictor of responsiveness to this class of agents. We show cleavage of PARP in response to treatment with Topo I inhibitors in colon cancer both in vitro and in vivo: (a) in vitro in SW480, HCT116, VACO5, VACO6, VACO8, VACO411, VACO425, and VACO451 human colon cancer cell lines treated with topotecan (TPT) or CPT-11; (b) in vivo in SW480, VACO451, and VRC5 colon cancer xenografts grown in athymic mice treated with TPT or CPT-11; and (c) in vivo in colon cancer samples from patients undergoing a Phase II clinical trial with CPT-11. Our results show a strong correlation between percentage of PARP cleavage and percentage of acridine orange-positive cells in colon cancer cell lines treated with 0.1 microM TPT for 24 and 48 h, confirming that PARP cleavage is a useful marker for programmed cell death in colon cancer cell lines. Results from experiments performed on colon cancer xenografts also show an association between PARP cleavage and response to treatment with TPT or CPT-11. The increase of PARP cleavage in xenografts and in clinical samples corresponding to treatment with Topo I inhibitors suggests that this procedure may have early predictive value to assess effectiveness of treatment. These results provide the basis for determining the validity of using PARP cleavage as an early marker of chemotherapeutic effectiveness in human samples.
半胱天冬酶对聚（ADP - 核糖）聚合酶（PARP）的切割是细胞凋亡或程序性细胞死亡的一个显著特征，已表明其可由拓扑异构酶（Topo）抑制剂诱导产生。由于Topo I抑制剂已被证明对某些结肠癌患者的治疗有效，我们考虑了将PARP切割作为对这类药物反应性早期预测指标的可能性。我们展示了在体外和体内，结肠癌对Topo I抑制剂治疗的反应中PARP的切割情况：（a）体外，在用拓扑替康（TPT）或伊立替康（CPT - 11）处理的SW480、HCT116、VACO5、VACO6、VACO8、VACO411、VACO425和VACO451人结肠癌细胞系中；（b）体内，在用TPT或CPT - 11处理的无胸腺小鼠中生长的SW480、VACO451和VRC5结肠癌异种移植瘤中；以及（c）体内，在接受CPT - 11 II期临床试验的患者的结肠癌样本中。我们的结果表明，在用0.1 microM TPT处理24小时和48小时的结肠癌细胞系中，PARP切割百分比与吖啶橙阳性细胞百分比之间存在很强的相关性，证实PARP切割是结肠癌细胞系中程序性细胞死亡的一个有用标志物。对结肠癌异种移植瘤进行的实验结果也显示了PARP切割与对TPT或CPT - 11治疗的反应之间的关联。与Topo I抑制剂治疗相对应的异种移植瘤和临床样本中PARP切割的增加表明，该过程可能对评估治疗效果具有早期预测价值。这些结果为确定将PARP切割用作人类样本中化疗有效性早期标志物的有效性提供了依据。
