Logan Richard M, Stringer Andrea M, Bowen Joanne M, Gibson Rachel J, Sonis Stephen T, Keefe Dorothy M K
Discipline of Oral Pathology, School of Dentistry, Faculty of Health Sciences, The University of Adelaide, North Terrace, Adelaide, SA 5005, Australia.
Cancer Chemother Pharmacol. 2009 Jan;63(2):239-51. doi: 10.1007/s00280-008-0732-8. Epub 2008 Mar 20.
Alimentary tract (AT) mucositis is a serious problem complicating cancer treatment, however, its pathobiology remains incompletely understood. Nuclear factor-kappaB (NF-kappaB) and pro-inflammatory cytokines are considered to have important roles in its development. This has been previously demonstrated in different sites of the AT following administration of irinotecan in an animal model using the Dark Agouti rat. The aim of the present study was to determine whether the changes that occur in the AT are affected by the type of mucotoxic drug.
Female DA rats were given a single dose of either methotrexate (1.5 mg/kg intramuscularly) or 5-fluorouracil (150 mg/kg intraperitoneally). Rats were killed at 30, 60, 90 min, 2, 6, 12, 24, 48 and 72 h. Control rats received no treatment. Samples of oral mucosa, jejunum and colon were collected. Haematoxylin and eosin stained sections were examined with respect to histological evidence of damage and standard immunohistochemical techniques were used to demonstrate tissue expression of NF-kappaB, TNF, IL-1beta and IL-6.
Both MTX and 5-FU administration caused histological evidence of tissue damage in the AT as well as changes in tissue expression of NF-kappaB and specific pro-inflammatory cytokines. This study, however, demonstrated that there were differences in the timing of histological changes as well as the timing and intensity of pro-inflammatory cytokine tissue expression caused by the different drugs.
The results from this study suggest that there are differences in the mucositis pathobiology caused by different drugs. This may have important ramifications for the management of mucositis particularly with respect to the development of treatment regimens for mucositis. Further investigations are required to determine the exact pathways that lead to damage caused by the different drugs.
消化道（AT）黏膜炎是癌症治疗中一个严重的并发症问题，然而，其病理生物学仍未完全明确。核因子-κB（NF-κB）和促炎细胞因子被认为在其发展过程中起重要作用。此前在使用黑褐大鼠的动物模型中，给予伊立替康后已在AT的不同部位证实了这一点。本研究的目的是确定AT中发生的变化是否受黏膜毒性药物类型的影响。
给雌性DA大鼠单次注射甲氨蝶呤（1.5mg/kg肌肉注射）或5-氟尿嘧啶（150mg/kg腹腔注射）。在30、60、90分钟、2、6、12、24、48和72小时处死大鼠。对照大鼠不接受治疗。收集口腔黏膜、空肠和结肠样本。苏木精和伊红染色切片用于检查损伤的组织学证据，并使用标准免疫组织化学技术来显示NF-κB、TNF、IL-1β和IL-6的组织表达。
甲氨蝶呤和5-氟尿嘧啶的给药均导致AT出现组织损伤的组织学证据以及NF-κB和特定促炎细胞因子的组织表达变化。然而，本研究表明，不同药物引起的组织学变化时间以及促炎细胞因子组织表达的时间和强度存在差异。
本研究结果表明，不同药物引起的黏膜炎病理生物学存在差异。这可能对黏膜炎的管理具有重要影响，特别是在黏膜炎治疗方案的制定方面。需要进一步研究以确定导致不同药物造成损伤的确切途径。
