Role of the cyclooxygenase pathway in chemotherapy-induced oral mucositis: a pilot study

Abstract

Goals: 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.

Materials and methods: 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.

Main results: 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.

Conclusions: 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.

Fig. 1

Mechanisms whereby the cyclooxygenase pathway mediates tissue injury and pain

Fig. 2

Mean (±SD) oral mucosal injury scores of the three subjects, at the different time-points before and after administration of high-dose chemotherapy. These mean scores were obtained by calculating an average of the total Oral Mucositis Index score for each subject, at each time-point

Fig. 3

Mean (±SD) mouth pain scores of the three subjects, at the different time-points before and after administration of high-dose chemotherapy. These mean scores were obtained by calculating an average of the Visual Analog Scale pain score for each subject, at each time-point

Fig. 4

Mean (±SD) tissue levels of cyclooxygenase-1 (COX-1) mRNA of the three subjects at the different time-points before and after administration of high-dose chemotherapy. These mean scores were obtained by calculating an average of the normalized cyclooxygenase-1 mRNA levels (in nanograms) obtained by RT-PCR, for each subject, at each time-point

Fig. 5

Mean (±SD) tissue levels of cyclooxygenase-2 (COX-2) mRNA of the three subjects at the different time-points before and after administration of high-dose chemotherapy. These mean scores were obtained by calculating an average of the normalized cyclooxygenase-2 mRNA levels (in nanograms) obtained by RT-PCR, for each subject, at each time-point

Fig. 6

Mean (±SD) tissue levels of microsomal prostaglandin E synthase (mPGES) mRNA of the three subjects at the different time-points before and after administration of high-dose chemotherapy. These mean scores were obtained by calculating an average of the normalized mPGES mRNA levels (in nanograms) obtained by RT-PCR, for each subject, at each time-point

Fig. 7

Mean (±SD) salivary PGE1 levels of the three subjects at the different time-points before and after administration of high-dose chemotherapy. These mean scores were obtained by calculating an average of the PGE1 levels (in picograms per milliliter) obtained by ELISA, for each subject, at each time-point

Fig. 8

Mean (±SD) salivary prostacyclin (PGI2) levels of the three subjects at the different time-points before and after administration of high-dose chemotherapy. These mean scores were obtained by calculating an average of the PGI2 levels (in picograms per milliliter) obtained by ELISA, for each subject, at each time-point