Section of Oral Medicine, Department of Oral Health and Diagnostic Sciences, Head & Neck/Oral Oncology Program, Neag Comprehensive Cancer Center, University of Connecticut Health Center, MC 1605, Room L6062, 263, Farmington Avenue, Farmington, CT 06030, USA.
Support Care Cancer. 2010 Jan;18(1):95-103. doi: 10.1007/s00520-009-0635-1. Epub 2009 Apr 29.
Oral mucositis can be a significant and dose-limiting complication of high-dose cancer therapy. Mucositis is a particularly severe problem in patients receiving myeloablative chemotherapy prior to bone marrow or hematopoetic stem cell transplant (HSCT). The cyclooxygenase (COX) pathway mediates tissue injury and pain through upregulation of pro-inflammatory prostaglandins, including prostaglandin E2 (PGE2) and prostacyclin (PGI2). The objective of this small (n = 3) pilot study was to examine the role of the COX pathway in causing mucosal injury and pain in chemotherapy-induced oral mucositis.
We collected blood, saliva, and oral mucosal biopsy specimens from three autologous HSCT patients at the following time-points before and after administration of conditioning chemotherapy: Day -10, +10, +28, and +100, where day 0 is day of transplant. RNA extracted from full-thickness tissue samples was measured by RT-PCR for the following: COX-1, COX-2, microsomal prostaglandin E synthase (mPGES), IL-1beta, and TNF-alpha. Blood and saliva samples were measured by ELISA for PGE2 and PGI2, which are markers of COX activity. Severity of oral mucositis was determined using the Oral Mucositis Index. Severity of pain due to oral mucositis was measured using a Visual Analog Scale. Relationships between the different variables were examined using Spearman rank correlation coefficients.
Mean mucositis and pain scores increased significantly after administration of chemotherapy and then gradually declined. The correlation between changes in mucositis and pain scores was strong and statistically significant. The following additional correlations were statistically significant: between tissue COX-1 and pain; between tissue mPGES and pain; between salivary PGE1 and pain; between salivary PGI2 and pain. Other relationships were not statistically significant.
Our finding of significant associations of pain scores with tissue COX-1 and mPGES, as well as salivary prostaglandins, is suggestive of a role for the cyclooxygenase pathway in mucositis, possibly via upregulation of pro-inflammatory prostaglandins. However, our small sample size may have contributed to the lack of significant associations between COX-2 and other inflammatory mediators with mucosal injury and pain. Thus, additional studies with larger numbers of subjects are warranted to confirm the involvement of the cyclooxygenase pathway in chemotherapy-induced mucositis.
口腔黏膜炎是大剂量放化疗的一种严重且剂量限制的并发症。骨髓或造血干细胞移植（HSCT）前接受骨髓清除性化疗的患者中，黏膜炎是一个特别严重的问题。环氧化酶（COX）途径通过上调致炎前列腺素（包括前列腺素 E2（PGE2）和前列环素（PGI2））介导组织损伤和疼痛。本小型（n=3）试验研究的目的是研究 COX 途径在化疗诱导的口腔黏膜炎中引起黏膜损伤和疼痛中的作用。
我们在接受预处理化疗前后的以下时间点从 3 名自体 HSCT 患者收集血液、唾液和口腔黏膜活检标本：-10 天、+10 天、+28 天和+100 天，其中 0 天为移植日。从全厚组织样本中提取的 RNA 通过 RT-PCR 测量以下指标：COX-1、COX-2、微粒体前列腺素 E 合酶（mPGES）、IL-1β和 TNF-α。通过 ELISA 测量血液和唾液样本中的 PGE2 和 PGI2，这是 COX 活性的标志物。使用口腔黏膜炎指数（Oral Mucositis Index）确定口腔黏膜炎的严重程度。使用视觉模拟量表（Visual Analog Scale）测量口腔黏膜炎引起的疼痛程度。使用 Spearman 等级相关系数检查不同变量之间的关系。
化疗后口腔黏膜炎和疼痛评分显著增加，然后逐渐下降。黏膜炎和疼痛评分的变化之间存在很强的统计学显著相关性。以下额外的相关性具有统计学意义：组织 COX-1 与疼痛之间；组织 mPGES 与疼痛之间；唾液 PGE1 与疼痛之间；唾液 PGI2 与疼痛之间。其他关系没有统计学意义。
我们发现疼痛评分与组织 COX-1 和 mPGES 以及唾液前列腺素之间存在显著关联，提示环氧化酶途径在黏膜炎中可能起作用，可能是通过上调致炎前列腺素。然而，我们的小样本量可能导致 COX-2 与其他炎症介质与黏膜损伤和疼痛之间缺乏显著关联。因此，需要进行更多的研究，以证实环氧化酶途径在化疗诱导的黏膜炎中的参与。
