Elsevier

Oral Oncology

Volume 43, Issue 4, April 2007, Pages 395-401
Oral Oncology

Nuclear factor-κB (NF-κB) and cyclooxygenase-2 (COX-2) expression in the oral mucosa following cancer chemotherapy

https://doi.org/10.1016/j.oraloncology.2006.04.011Get rights and content

Summary

Oral mucositis is a serious and debilitating side effect of cancer treatment. Greater understanding of the pathobiology of mucositis has recently led to the advent of targeted treatments for specific patient populations; however the treatment for mucositis remains palliative for most patients. Nuclear factor-kappaB (NF-κB) and cyclooxygenase 2 (COX-2) are thought to play important roles in the development of mucositis. In this study, 20 patients undergoing cytotoxic chemotherapy had oral mucosal biopsies taken prior to and following administration of cytotoxic chemotherapy. The samples were stained for NF-κB and COX-2 using routine immunohistochemistry. The results from this preliminary study demonstrated statistically significant increased oral mucosal staining for NF-κB and COX-2 following cytotoxic chemotherapy and provide further support for the role of NF-κB and COX-2 in the pathogenesis of mucositis.

Introduction

Mucositis is a debilitating side effect of various types of cancer treatment and encompasses the entire gastrointestinal tract (GIT) from mouth to anus. It manifests in the oral cavity as a spectrum of clinical signs ranging from generalised erythema to widespread ulceration often rendering alimentation impossible due to pain.1, 2, 3 In the small and large intestines, mucositis results in abdominal bloating as well as vomiting and diarrhoea.4, 5, 6, 7 Whilst there have been recent developments of targeted treatments in specific clinical settings8, the treatment for oral mucositis in most patients is still largely palliative involving pain relief and maintenance of good oral hygiene.2, 3, 9 In addition to the quality of life issues that it causes, mucositis also has serious economic consequences for the provision of treatment10 and may also have a negative effect on treatment outcomes due to the need for treatment cessation or modification due to mucositis.11 Furthermore, treatment for mucositis such as narcotic analgesics, also have an impact on patient well-being and quality of life during treatment.12 It is important therefore that the pathogenesis of this side effect of cancer treatment is accurately determined so that effective treatments can be provided to treat and prevent its occurrence.

Much of the previous research into mucositis has involved the use of animal models and there is a distinct paucity of research in the literature relating to mucositis pathobiology in the clinical setting. A recent study by Gibson et al.13 provided data on morphological and ultrastructural changes in the oral mucosa following cytotoxic chemotherapy. This study demonstrated that the level of apoptosis occurring in the oral mucosa peaked at 3 days following chemotherapy and this was 400 times the level seen in the healthy controls. Likewise ultrastructural changes occurred in the mucosa and persisted up to 11 days following chemotherapy. Gibson’s data support the 5 stage hypothesis of mucositis pathogenesis in which transcription factors activated by chemotherapy, radiation therapy or reactive oxygen species play a major role in the biological cascade that leads to mucosal injury.11, 14 In the context of mucositis, the transcription factor NF-κB is considered to be one of the main “drivers” of the condition. Its activation results in the upregulation of a variety of genes and subsequent production of pro-inflammatory cytokines including tumor necrosis factor-alpha, interleukin-1β and interleukin-6, which results in increased tissue injury in all compartments of the mucosa, not exclusively the epithelium. In addition, NF-κB also causes upregulation of COX-2 which has also been implicated in increasing levels of matrix metalloproteinases, a likely mediator of tissue damage.14 It is thought that the subsequent amplification of these biological events via positive feedback loops, as well as stimulation by bacterial cell wall products, result in the widespread tissue damage seen in the clinical setting as ulceration. The finding that NF-κB expression and COX-2 levels were elevated in the irradiated colorectum in association with histopathological changes consistent with mucositis provides further support for a role for NF-κB in regimen-related mucosal barrier injury.15 The authors suggest that the underlying mechanisms of mucosal tissue injury in the oral and colorectal region are similar. The purpose of the current study was to characterise the expression of NF-κB and COX-2 in the human oral mucosa following cytotoxic chemotherapy.

Section snippets

Materials and methods

Twenty adult patients scheduled to receive cytotoxic chemotherapy for the treatment of non-head and neck solid tumours were studied.13 Standard dose chemotherapy using multiple drug regimens known to be associated with mucositis was administered to all patients over a 1–4 hour time period (Table 1). Four healthy adults (one male and three females) with no history of cancer or previous chemotherapy, served as controls. The study was approved by the Ethics of Human Research Committee of the Royal

Patients

Four male and sixteen female subjects with a median age of 52.4 years were enrolled for study. Patients received a range of chemotherapy regimens for a variety of tumor diagnoses (Table 1).

With the exception of one subject who noted post-biopsy soreness and withdrew from the study, study subjects tolerated the procedure well. One subject did not receive their anticipated cancer therapy and was consequently dropped from the study after their pre-treatment biopsy. Post-chemotherapy biopsies were

Discussion

There has been substantial literature published on various management strategies to treat oral mucositis. However there has been a paucity of data reporting the mechanistic aspects of the development or pathobiology of oral mucositis, particularly in the clinical setting. The present study examined the expression of NF-κB and COX-2 in the oral mucosa of patients following cytotoxic chemotherapy. Although preliminary, this study demonstrated that NF-κB and COX-2 were elevated following

Acknowledgements

The funding for this project has been provided by the Australian Dental Research Fund Incorporated. The authors would like to acknowledge Professor G. Townsend and Dr. T Hughes (School of Dentistry, The University of Adelaide) for their assistance in the statistical analysis of the data.

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      Activation of the NF-κB signaling and MAPK signaling pathways,7 as well as continued synthesis and release of inflammatory cytokines, results in the loss of mucosal integrity along the GI tract.7,28 Consistent with these mechanisms, we found perturbations in three pathways (i.e., cytokine-cytokine receptor interaction, MAPK signaling, NF-κB signaling) that have preclinical29–31 and clinical32 evidence to support their involvement in GI inflammation. In terms of cytokine-cytokine receptor interactions, in two preclinical studies, CTX-induced mucositis was associated with an increase in tumor necrosis factor alpha (TNF-α) immunostaining29 as well as with increases in the expression of TNF-α and interleukin-6 (IL-6).31

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