Abstract

Background

Olaparib, a poly [ADP-ribose] polymerase (PARP) inhibitor, is used in cancer treatment and in other diseases and achieves local cancer control in combination with radiotherapy.

Objectives

We investigated the effects of olaparib on irradiation-induced intestinal damage using both in vitro and in vivo model systems. In particular, we evaluated how olaparib affects irradiation-induced cytotoxicity in intestinal epithelial (IEC-6) cell line and intestinal damage in mice subjected to abdominal radiation.

Results

Using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays to evaluate radiation-induced cytotoxicity and the loss of cell viability, we found that olaparib pretreatment significantly exacerbated radiation-induced effects. Olaparib therapy increased protein expression related to radiation-induced DNA damage. Administering per oral olaparib (100 mg/kg) to adult mice from − 2 to 0 days before radiation exposure (10 or 15 Gy) significantly accelerated intestinal damage. Measurements of the small intestinal villi length and number of crypts were collected through histological investigations. The irradiation group showed shorter crypt survival and jejunal villi height than the sham-irradiated group. In addition, through the TUNEL assay, we were able to confirm an increased apoptotic rate of enterocytes in the group pretreated with olaparib before 10 Gy of irradiation compared with the dose-matched irradiation group.

Conclusion

In radiation-exposed mice, olaparib therapy significantly reduced indicators such as the length of the small intestinal villi and number of crypts. Administering olaparib before radiation aggravated the radiation-induced damage to the jejunum and exacerbated intestinal apoptosis. Olaparib in combination with radiotherapy should be used cautiously in patients with cancer.

中文翻译：

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奥拉帕尼协同加剧辐射诱导的小鼠肠道细胞凋亡

摘要

背景

奥拉帕尼是一种聚[ADP-核糖]聚合酶（PARP）抑制剂，用于癌症治疗和其他疾病，并与放射治疗相结合实现局部癌症控制。

目标

我们使用体外和体内模型系统研究了奥拉帕尼对辐射引起的肠道损伤的影响。特别是，我们评估了奥拉帕尼如何影响肠上皮（IEC-6）细胞系中辐射诱导的细胞毒性以及腹部辐射小鼠的肠道损伤。

结果

使用 3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四唑溴化物和乳酸脱氢酶测定来评估辐射诱导的细胞毒性和细胞活力的丧失，我们发现奥拉帕尼预处理显着加剧了辐射诱导的效应。奥拉帕尼治疗增加了与辐射诱导的 DNA 损伤相关的蛋白质表达。在辐射暴露（10 或 15 Gy）前 2 至 0 天，对成年小鼠口服奥拉帕尼（100 mg/kg）会显着加速肠道损伤。通过组织学研究收集小肠绒毛长度和隐窝数量的测量结果。与假照射组相比，照射组的隐窝存活率和空肠绒毛高度较短。此外，通过TUNEL实验，我们能够证实，与剂量匹配照射组相比，在10 Gy照射前用奥拉帕尼预处理的组肠细胞凋亡率增加。

结论

在暴露于辐射的小鼠中，奥拉帕尼治疗显着降低了小肠绒毛长度和隐窝数量等指标。放疗前给予奥拉帕尼会加重放疗引起的空肠损伤，并加剧肠细胞凋亡。癌症患者应谨慎使用奥拉帕尼与放疗联合使用。