Cariveau Mickael J, Stackhouse Murray, Cui Xiao-Li, Tiwari Kamal, Waud William, Secrist John A, Xu Bo
Department of Biochemistry and Molecular Biology, Southern Research Institute, Birmingham, AL 35205, USA.
Int J Radiat Oncol Biol Phys. 2008 Jan 1;70(1):213-20. doi: 10.1016/j.ijrobp.2007.09.012. Epub 2007 Nov 26.
Combination treatment with radiotherapy and chemotherapy has emerged as the dominant form of cancer adjuvant regimens in recent years. Clofarabine, a newly approved drug for pediatric leukemia, is a second-generation purine nucleoside analogue that can block DNA synthesis and inhibit DNA repair. Therefore, we hypothesized that clofarabine could work synergistically with radiotherapy to increase the tumor cell response.
The effects of clofarabine on radiosensitivity have been established in several tumor cell lines in vitro and in vivo using colony-forming assays and tumor xenografts. The effect of clofarabine on the DNA damage response was also studied in vitro by measuring gamma-H2AX focus formation.
Clonogenic survival was significantly reduced in irradiated cells treated with clofarabine, demonstrating the strong radiosensitizing effect of clofarabine. Furthermore, clofarabine displayed a radiosensitizing effect that was greater than gemcitabine or 5-fluorouracil. We also found that low doses of clofarabine can prolong the presence of radiation-induced gamma-H2AX nuclear focus formation, and high doses of clofarabine can induce DNA double-strand breaks, suggesting that clofarabine can interfere with DNA damage response pathways. In addition, clofarabine-induced radiosensitization was also established in vivo using a colorectal cancer model, DLD-1, in athymic nude mice. When combined with fractionated radiotherapy, a moderate dose of clofarabine led to a significant increase in tumor growth inhibition.
Clofarabine acts as a powerful radiosensitizer both in vitro and in vivo by interfering with the DNA damage response.
近年来，放疗与化疗联合治疗已成为癌症辅助治疗方案的主要形式。氯法拉滨是一种新批准用于治疗儿童白血病的药物，是第二代嘌呤核苷类似物，可阻断DNA合成并抑制DNA修复。因此，我们推测氯法拉滨可与放疗协同作用，增强肿瘤细胞反应。
通过集落形成试验和肿瘤异种移植，在体外和体内的多种肿瘤细胞系中确定了氯法拉滨对放射敏感性的影响。还通过测量γ-H2AX焦点形成，在体外研究了氯法拉滨对DNA损伤反应的影响。
用氯法拉滨处理的受照射细胞的克隆形成存活率显著降低，表明氯法拉滨具有强大的放射增敏作用。此外，氯法拉滨的放射增敏作用大于吉西他滨或5-氟尿嘧啶。我们还发现，低剂量的氯法拉滨可延长辐射诱导的γ-H2AX核焦点形成的持续时间，高剂量的氯法拉滨可诱导DNA双链断裂，这表明氯法拉滨可干扰DNA损伤反应途径。此外，在无胸腺裸鼠的结直肠癌模型DLD-1中，也证实了氯法拉滨在体内具有放射增敏作用。当与分割放疗联合使用时，中等剂量的氯法拉滨可显著增强肿瘤生长抑制作用。
氯法拉滨通过干扰DNA损伤反应，在体外和体内均发挥强大的放射增敏作用。
