Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA.
Comparative Hepatobiliary and Intestinal Research Program (CHIRP), College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA.
Vet Med Sci. 2021 Mar;7(2):385-392. doi: 10.1002/vms3.392. Epub 2020 Nov 22.
Gastrointestinal (GI) toxicosis is a common side effect of cytotoxic chemotherapy treatment in humans and dogs. Measurement of cytokeratin 18 (CK18), an intracellular structural protein released during epithelial apoptosis, and Alpha1-Antitrypsin (A1AT) in faeces provides a mechanism for evaluating damage to the intestinal mucosa secondary to cytotoxic chemotherapy. Our goal was to evaluate the clinical utility of plasma CK18 and faecal A1-AT levels as non-invasive biomarkers of cytotoxic chemotherapy induced GI toxicity. We conducted a prospective cohort study in dogs (N = 10) with osteosarcoma undergoing amputation followed by carboplatin chemotherapy. We hypothesized that plasma CK18 and faecal A1-AT levels would increase following carboplatin administration due to drug-induced GI epithelial damage/apoptosis, and that plasma CK18 and faecal A1-AT levels would correlate with severity of GI toxicity. Mean baseline plasma CK18 concentration was variable amongst patients; however, CK18 concentration prior to carboplatin chemotherapy treatment was not significantly different from CK18 levels after treatment. There was significant intra and inter-patient variability in mean faecal A1-AT levels at baseline. Mean A1-AT concentration did not change significantly from day 0 to day 21. Gastrointestinal toxicity was minimal; therefore, we were unable to determine the association of plasma CK18 and faecal A1-AT concentrations with development of GI toxicosis. In this study population, plasma CK18 and faecal A1-AT concentration were not clinically useful biomarkers for the detection of GI toxicosis secondary to carboplatin administration. Further prospective evaluation of CK18 and A1-AT as biomarkers of drug-induced GI toxicity is warranted in a larger cohort of dogs receiving cytotoxic chemotherapy. AVMA clinical trial registration number: AAHSD004827.
胃肠道（GI）中毒是人类和犬类细胞毒性化疗治疗的常见副作用。细胞角蛋白 18（CK18）的测量，这是一种细胞内结构蛋白，在上皮细胞凋亡过程中释放，以及粪便中的 Alpha1-Antitrypsin（A1AT）为评估细胞毒性化疗引起的肠黏膜损伤提供了一种机制。我们的目标是评估血浆 CK18 和粪便 A1AT 水平作为细胞毒性化疗引起的胃肠道毒性的非侵入性生物标志物的临床实用性。我们对接受截肢手术和随后接受卡铂化疗的骨肉瘤犬（N=10）进行了前瞻性队列研究。我们假设，由于药物引起的胃肠道上皮损伤/凋亡，卡铂给药后血浆 CK18 和粪便 A1AT 水平会增加，并且血浆 CK18 和粪便 A1AT 水平与胃肠道毒性的严重程度相关。患者之间的平均基线血浆 CK18 浓度各不相同；然而，卡铂化疗前的 CK18 浓度与治疗后的 CK18 水平没有显著差异。基线时粪便 A1AT 水平的个体内和个体间差异显著。A1AT 浓度从第 0 天到第 21 天没有显著变化。胃肠道毒性极小；因此，我们无法确定血浆 CK18 和粪便 A1AT 浓度与胃肠道毒性发展的关系。在本研究人群中，血浆 CK18 和粪便 A1AT 浓度对于检测卡铂给药引起的胃肠道毒性并不具有临床实用性生物标志物。需要在接受细胞毒性化疗的更大犬科动物队列中进一步前瞻性评估 CK18 和 A1AT 作为药物引起的胃肠道毒性的生物标志物。AVMA 临床试验注册号：AAHSD004827。
