Jongbloed Franny, Huisman Sander A, van Steeg Harry, Pennings Jeroen L A, IJzermans Jan N M, Dollé Martijn E T, de Bruin Ron W F
Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.
Laboratory for Health Protection Research, National Institute of Public Health and The Environment, Bilthoven, The Netherlands.
Oncotarget. 2019 Mar 15;10(22):2224-2234. doi: 10.18632/oncotarget.26776.
Irinotecan use is limited due to severe toxicity. Preconditioning by fasting (PBF) protects against side effects of irinotecan while preserving its antitumor activity. The mechanisms underlying the effects of PBF still need to be elucidated. Here, we investigated the transcriptional responses of PBF on irinotecan in both tumor and healthy liver tissue.
Male BALB/c mice were subcutaneously injected with C26 colon carcinoma cells. Twelve days after tumor inoculation, two groups were fasted for three days and two groups were allowed food ad libitum (AL). Subsequently, both groups received one dose of irinotecan. Twelve hours after administration mice were sacrificed and blood, tumor and liver tissue were harvested. Blood samples were analyzed to determine liver, kidney and bone marrow function, tissues were used for transcriptome analyses.
The AL irinotecan group showed worsened organ function and decreased leukocyte numbers. These effects were abated in PBF animals. PBF led to an altered transcriptional response in the liver of irinotecan-treated mice, including decreased cellular injury and increased stress resistance. Hepatic metabolism of irinotecan was also significantly changed due to PBF. The transcriptional response of tumor tissue observed after PBF was hardly affected compared to AL fed animals.
Transcriptional changes after PBF to irinotecan treatment showed an improved protective stress response in healthy liver but not in tumor tissue, including changes in irinotecan metabolism. These data help to unravel the mechanisms underlying the effects of fasting on irinotecan and help to improve outcome of chemotherapeutic treatment in cancer patients.
由于严重的毒性，伊立替康的使用受到限制。禁食预处理（PBF）可预防伊立替康的副作用，同时保留其抗肿瘤活性。PBF作用的潜在机制仍有待阐明。在此，我们研究了PBF对肿瘤和健康肝脏组织中伊立替康的转录反应。
雄性BALB/c小鼠皮下注射C26结肠癌细胞。肿瘤接种12天后，两组禁食三天，两组自由进食（AL）。随后，两组均接受一剂伊立替康。给药12小时后处死小鼠，采集血液、肿瘤和肝脏组织。分析血样以确定肝脏、肾脏和骨髓功能，组织用于转录组分析。
AL伊立替康组显示器官功能恶化，白细胞数量减少。这些影响在PBF动物中减轻。PBF导致伊立替康治疗小鼠肝脏中的转录反应发生改变，包括细胞损伤减少和应激抗性增加。由于PBF，伊立替康的肝脏代谢也发生了显著变化。与AL喂养的动物相比，PBF后观察到的肿瘤组织转录反应几乎没有受到影响。
PBF对伊立替康治疗后的转录变化显示，健康肝脏中的保护性应激反应得到改善，但肿瘤组织中未改善，包括伊立替康代谢的变化。这些数据有助于揭示禁食对伊立替康作用的潜在机制，并有助于改善癌症患者的化疗治疗效果。
