Systematic review of agents for the management of cancer treatment-related gastrointestinal mucositis and clinical practice guidelines.

PURPOSE: The aim of this study was to update the clinical practice guidelines for the use of agents for the prevention and/or treatment of gastrointestinal mucositis (GIM). METHODS: A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: Recommendation, Suggestion, and No Guideline Possible. RESULTS: A total of 78 papers across 13 interventions were examined of which 25 were included in the final review. No new guidelines were possible for any agent due to inadequate and/or conflicting evidence. Existing guidelines for probiotics and hyperbaric oxygen were unchanged. CONCLUSIONS: Of the agents studied for the prevention and treatment of GIM, the evidence continues to support use of probiotics containing Lactobacillus spp. for prevention of chemoradiotherapy and radiotherapy-induced diarrhea in patients with pelvic malignancy, and hyperbaric oxygen therapy to treat radiation-induced proctitis. Additional well-designed research is encouraged to enable a decision regarding palifermin, glutamine, sodium butyrate, and dietary interventions, for the prevention or treatment of GIM.

Matrix metalloproteinase expression is altered in the small and large intestine following fractionated radiation in vivo.

PURPOSE: Radiotherapy-induced gut toxicity (RIGT) is associated with significant diarrhoea, pain and rectal bleeding. Matrix metalloproteinases (MMPs) have been reported to be involved in chemotherapy-induced gut toxicity and RIGT following single-dose irradiation in vivo. We therefore proposed MMPs would be involved in the pathobiology of RIGT following fractionated irradiation. METHODS: Dark Agouti rats were treated with fractionated radiation (3 × 2.5 Gy/week for 6 weeks). Rats were killed at 3, 6 and 15 weeks to represent acute and chronic toxicities. Sections of jejunum and colon were immunostained for MMP-1, MMP-2, MMP-9 and MMP-14. Relative mRNA expression in jejunum and colon was quantified by RT-PCR for MMP-1, MMP-2, MMP-9 and MMP-14. Western blotting was also conducted on jejunum and colon tissue collected at week 6 to determine protein levels of pro- and active MMP-2. RESULTS: MMP-2 total protein levels, determined by western blotting, significantly increased in both the jejunum (p = 0.0359) and the colon (p = 0.0134) 6 weeks into the fractionated radiation schedule. MMP-1, MMP-2, and MMP-14 mRNA expression significantly increased in the jejunum. MMP-2 mRNA expression was also significantly increased in the colon. Immunostaining of MMP-2 was observed to be increased in both crypt enterocytes and the lamina propria. CONCLUSIONS: MMP-2 plays a role in the pathobiology of gastrointestinal toxicities following fractionated irradiation. Whilst MMP-1 and MMP-14 mRNA expression was increased, this occurred only in the jejunum, suggesting MMPs are differentially involved in RIGT depending on the intestinal region. Further studies are needed to elucidate the role these mediators play in the development and potentiation of RIGT.

Cell adhesion molecules are altered during irinotecan-induced mucositis: a qualitative histopathological study.

PURPOSE: Chemotherapy-induced mucositis is characterised by damage to mucous membranes throughout the alimentary tract. This study aims to investigate the expression of cell adhesion molecules (CAMs) following treatment with irinotecan. METHODS: Dark agouti rats received a single dose of 175 mg/kg irinotecan and sacrificed at various time points after treatment. Picro-sirius red staining indicated an increase in collagen around crypts from 24 h in both small and large intestinal regions and this diminished at the later time points. CAMs E-cadherin, P-selectin, E-selectin and integrin-α1 were examined using immunohistochemistry. RESULTS: E-cadherin was significantly elevated in jejunal crypts at the time of maximal tissue damage (48 h), while it decreased at the healing phase (96 h) in both jejunum and colon. P-selectin expression decreased significantly in the jejunum following irinotecan. Crypt expression of E-selectin was significantly elevated in the healing phase of mucositis (96 h). Integrin-α1 expression was significantly altered during the time course in the villus (p = 0.0032) and lamina propria (p = 0.039). CONCLUSIONS: Irinotecan induced a significant alteration in CAM expression in the jejunum and colon. Changes in adhesion molecule expression may have a direct impact on the loss of mucosal layer integrity seen in mucositis.

Fractionated abdominal irradiation induces intestinal microvascular changes in an in vivo model of radiotherapy-induced gut toxicity.

PURPOSE: Radiotherapy-induced gut toxicity (RIGT) is associated with diarrhoea, pain and rectal bleeding and can occur as an acute or chronic toxicity. The microvasculature has been shown to be altered in the development of RIGT; however, the features are not yet characterized. We hypothesized that apoptosis of microvascular cells would occur early in the gastrointestinal tract following fractionated irradiation, followed by late microvascular changes, including sclerosis and telangiectasis. METHODS: Female Dark Agouti rats were treated with a 6-week fractionated radiation schedule of 3 × 2.5 Gy doses per week localized to the abdomen. At 3, 6 and 15 weeks, the intestines were assessed for markers of acute and chronic injury including morphological changes, collagen deposition, apoptosis and proliferation. RESULTS: Apoptosis of microvascular cells significantly increased at 6 and 15 weeks in the jejunum (p = 0.0026 and p = 0.0062, respectively) and at 6 and 15 weeks in the colon (p < 0.0001 and p = 0.0005, respectively) in rats receiving fractionated radiation to the abdomen. Histopathological changes of the colon microvasculature were also seen from week 3, including thickening of the lamina propria and dilated, thickened, telangiectatic vessels. CONCLUSIONS: Findings of this study provide evidence of regional and timing-specific changes in the intestinal microvasculature in response to fractionated radiotherapy which may play a role in development of both acute and chronic RIGT.

The multifunctional alarmin HMGB1 with roles in the pathophysiology of sepsis and cancer.

Although originally described as a highly conserved nuclear protein involved in DNA replication, transcription and repair, high-mobility group box-1 protein (HMGB1) has emerged as a key mediator in the regulation of immune responses to infection and sterile injury by exhibiting all the properties of a prototypic 'alarmin'. These include rapid passive release in response to pathogenic infection and/or traumatic injury, active secretion providing for chemotactic and cytokine-like function and an ability to resolve inflammation, including tissue repair and remodelling. In this review, we will give an overview of the post-translational modifications necessary for such diversity in biological activity, concentrating particularly on how differences in oxidation of highly conserved redox-sensitive cysteine residues can potentiate inflammatory responses and dictate cellular fate. We will also review the most recent literature on HMGB1 and its involvement in the pathophysiology of sepsis and cancer, as well as cancer therapy-induced mucositis.

Biomarkers of chemotherapy-induced diarrhoea: a clinical study of intestinal microbiome alterations, inflammation and circulating matrix metalloproteinases.

PURPOSE: A common side effect of chemotherapy treatment is diarrhoea. Unfortunately, the underlying mechanisms of chemotherapy-induced diarrhoea (CD) are poorly understood. We aimed to determine if faecal microbes of CD patients were displaced, if faecal calprotectin increased during CD and if there were alterations in circulating matrix metalloproteinases, nuclear factor kappa B (NF-κB), IL-1ß and TNF. PATIENTS AND METHODS: Twenty-six cancer patients receiving chemotherapy were enrolled and requested to provide stool samples and blood samples at various times during their chemotherapy cycle. Stool samples were analysed using conventional culture techniques and qRT-PCR. ELISA kits determined faecal calprotectin levels, levels of circulating matrix metalloproteinases and circulating NF-κB, IL-1ß and TNF. RESULTS: The majority of patients with CD showed decreases in Lactobacillus spp., Bifidobacterium spp., Bacteroides spp. and Enterococcus spp. Increases were observed in Escherichia coli and Staphylococcus spp. Methanogenic archaea were also quantified, with all patients except one showing a decrease. Faecal calprotectin levels were increased in 81.25 % of patients with CD. Circulating MMP-3 and MMP-9 significantly increased following chemotherapy. Circulating levels of NF-κB, IL-1ß and TNF were increased following chemotherapy, although this did not reach significance. CONCLUSIONS: We demonstrated that CD is associated with marked changes in intestinal microflora, methanogenic archaea, matrix metalloproteinase and serum levels of NF-κB, IL-1ß and TNF. These changes may result in diminished bacterial functions within the gut, altering gut function and initiating intestinal damage, resulting in the onset of diarrhoea. More importantly, these changes may provide clinicians with a possible new target for biomarkers of toxicity.

Emerging evidence on the pathobiology of mucositis.

BACKGROUND: Considerable progress has been made in our understanding of the biological basis for cancer therapy-induced mucosal barrier injury (mucositis). The last formal review of the subject by MASCC/ISOO was published in 2007; consequently, an update is timely. METHODS: Panel members reviewed the biomedical literature on mucositis pathobiology published between January 2005 and December 2011. RESULTS: Recent research has provided data on the contribution of tissue structure changes, inflammation and microbiome changes to the development of mucositis. Additional research has focused on targeted therapy-induced toxicity, toxicity clustering and the investigation of genetic polymorphisms in toxicity prediction. This review paper summarizes the recent evidence on these aspects of mucositis pathobiology. CONCLUSION: The ultimate goal of mucositis researchers is to identify the most appropriate targets for therapeutic interventions and to be able to predict toxicity risk and personalize interventions to genetically suitable patients. Continuing research efforts are needed to further our understanding of mucositis pathobiology and the pharmacogenomics of toxicity.

Emerging evidence on the pathobiology of mucositis.

BACKGROUND: Considerable progress has been made in our understanding of the biological basis for cancer therapy-induced mucosal barrier injury (mucositis). The last formal review of the subject by MASCC/ISOO was published in 2007; consequently, an update is timely. METHODS: Panel members reviewed the biomedical literature on mucositis pathobiology published between January 2005 and December 2011. RESULTS: Recent research has provided data on the contribution of tissue structure changes, inflammation and microbiome changes to the development of mucositis. Additional research has focused on targeted therapy-induced toxicity, toxicity clustering and the investigation of genetic polymorphisms in toxicity prediction. This review paper summarizes the recent evidence on these aspects of mucositis pathobiology. CONCLUSION: The ultimate goal of mucositis researchers is to identify the most appropriate targets for therapeutic interventions and to be able to predict toxicity risk and personalize interventions to genetically suitable patients. Continuing research efforts are needed to further our understanding of mucositis pathobiology and the pharmacogenomics of toxicity.

Irinotecan-induced alterations in intestinal cell kinetics and extracellular matrix component expression in the Dark Agouti rat.

Chemotherapy-induced mucositis is characterized by damage of mucous membranes throughout the alimentary tract (AT). Extracellular matrix (ECM) components play a vital role in maintaining mucosal barrier integrity by regulating cellular apoptosis, proliferation and differentiation of overlying epithelial cells. The aims of this study were to characterize the changes in epithelial cell kinetics and to investigate the expression of the ECM components in the gastrointestinal tract following irinotecan administration. Female dark agouti rats were treated with single 200 mg/kg dose irinotecan and killed at various time points (1, 6, 24, 48, 72, 96 and 14 h) after treatment. Ki67 immunostaining and TUNEL were used to assess proliferation and apoptosis, respectively, in the jejunum and colon. Masson trichrome staining and picro-sirius red staining were used to determine the level of collagen, and immunohistochemistry was used to further assess collagen IV, fibronectin and laminin 1 and 2 expression in these tissues. Irinotecan halved cellular proliferation in the jejunum and colon at 48 and 24 h, respectively, while apoptosis peaked at 6 h (P < 0.05). There was a substantial increase in total collagen deposits around crypts from 24 h in both regions. However, collagen IV expression decreased significantly in the crypt region in a delayed fashion (P < 0.05). Fibronectin expression decreased significantly in jejunum and colon from 6 to 24 h following treatment (P < 0.05). Irinotecan induced a significant alteration in epithelial cell kinetics in both the jejunum and colon, and this correlated with changes in ECM component expression. Changes in ECM expression may have a direct impact on the loss of mucosal layer integrity evident in chemotherapy-induced mucositis.

Selection of housekeeping genes for gene expression studies in a rat model of irinotecan-induced mucositis.

BACKGROUND/AIMS: Mucositis is the term used to describe damage caused by chemotherapy to mucous membranes of the alimentary tract. RT-PCR has recently been utilised to determine the molecular events that occur in mucositis. As this method relies on the use of a validated endogenous control, this study aims to validate commonly used housekeeping genes in an irinotecan-induced mucositis model. METHODS: Rats were administered irinotecan and sacrificed at different time points, in particular 1, 24, 72 and 144 h following treatment. Histopathological damage was assessed by haematoxylin and eosin staining. RT-PCR was used to evaluate the expression of 11 housekeeping genes. Expression stability was determined by the Normfinder program. Matrix metalloproteinase 2 was used as a target gene to validate the appropriateness of the top-ranking housekeeping gene. RESULTS: For normalisation to multiple housekeeping genes, the most stable combination across all time points in the jejunum was Ywhaz/UBC and in the colon UBC/ß-actin. SDHA and GAPDH were the most variable genes in the jejunum and colon where they were 4.4 and 3.2 fold upregulated following irinotecan, respectively. CONCLUSIONS: For normalisation of irinotecan-induced mucositis gene expression studies, a combination of Ywhaz/UBC and UBC/ß-actin should be used in the jejunum and colon, respectively. UBC is the most favourable if restricted to a single housekeeping gene across all time points.

Irinotecan-induced mucositis manifesting as diarrhoea corresponds with an amended intestinal flora and mucin profile.

Chemotherapy-induced diarrhoea is a major oncological problem, caused by the cytotoxic effects of cancer chemotherapy. Irinotecan is linked with severe mucositis and diarrhoea, the mechanisms of which remain poorly understood. Bacterial beta-glucuronidase is thought to be involved in the metabolism of irinotecan, implicating the intestinal flora. Intestinal mucins may also be implicated in the development of chemotherapy-induced diarrhoea. Rats were treated with 200 mg/kg of irinotecan and killed at 96, 120 and 144 h. The rats were monitored for diarrhoea. Pathology and immunohistochemical staining was performed. The samples were cultured and faecal DNA was analysed using real-time polymerase chain reaction. Severe diarrhoea was observed from 72 to 96 h. A decrease in body mass was also observed after treatment. Significant changes in goblet cell numbers (both complete and cavitated cells) were observed in the small and large intestines. Changes in MUC gene expression were observed in the small intestine only. Modifications were observed to the intestinal flora profile, especially Escherichia coli, and an increase in the expression of beta-glucuronidase was detected. In conclusion, irinotecan-induced diarrhoea may be caused by an increase in some beta-glucuronidase-producing bacteria, especially E. coli, exacerbating the toxicity of active metabolites. Accelerated mucous secretion and mucin release may also contribute to the delayed onset of diarrhoea.

Trastuzumab induces gastrointestinal side effects in HER2-overexpressing breast cancer patients.

PURPOSE: To characterise the gastrointestinal toxicities associated with Trastuzumab administration in HER2-overexpressing breast cancer patients. METHODS: All patients (n = 46) who received Trastuzumab as a single agent or in conjunction with conventional anti-cancer treatment within the Royal Adelaide Hospital Cancer Centre from 2002-2007 were included in this study. A retrospective analysis of case-notes was conducted to investigate the toxicities associated with Trastuzumab. RESULTS: Trastuzumab as a single agent induced toxicities following 22% of administrations. Gastrointestinal toxicities were observed following 12% of administrations and included nausea and vomiting, diarrhoea, abdominal pain and bloating. However, other prominent toxicities that were not related to the gastrointestinal tract were also observed including fatigue and lung symptoms (10.4%). Elderly patients (> or =60 years) and those with metastatic disease experienced the highest frequency of toxicity. CONCLUSION: Trastuzumab induces a range of gastrointestinal toxicities in HER2-overexpressing breast cancer patients. These toxicities are separate to those caused by concurrent chemotherapy and/or radiotherapy.

Vascular endothelial growth factor (VEGF), transforming growth factor beta (TGFß), angiostatin, and endostatin are increased in radiotherapy-induced gastrointestinal toxicity.

PURPOSE: Radiotherapy-induced gut toxicity (RIGT) is a debilitating effect of radiotherapy for cancer, often resulting in significant diarrhea and pain. Previous studies have highlighted roles of the intestinal microvasculature and matrix metalloproteinases (MMPs) in the development of RIGT. We hypothesized vascular mediators would be significantly altered in a dark agouti (DA) rat model of RIGT. Additionally, we aimed to assess the effect of MMP-2 and -9 inhibition on the response of tumor-associated microvascular endothelial cells (TAMECs) to radiation. METHODS: DA rats were administered 2.5 Gy abdominal irradiation (3 times/week over 6 weeks). Vascular endothelial growth factor (VEGF), transforming growth factor beta (TGFß), von Willebrand factor (VWF), angiostatin, and endostatin expression was assessed at 3, 6, and 15 weeks. Additionally, DA rat mammary adenocarcinoma tumor-associated microvascular endothelial cells (TAMECs) were used to assess the effects of radiation (12 Gy) and the MMP inhibitor SB-3CT on MMP, VEGF, and TGFß expression, and cell viability. RESULTS: VEGF mRNA expression was significantly increased in the colon at week 15 (p = .0012), and TGFß mRNA expression was significantly increased in both the jejunum and colon at week 3 (p = .0280 and p = .0310, respectively). Endostatin immunostaining was significantly increased at week 3 (p = .0046), and angiostatin at 3 and 6 weeks (p = .0022 and p = .0135, respectively). MMP-2 and -9 mRNA and total protein levels were significantly increased following irradiation of TAMECs. Although this increase was significantly attenuated by SB-3CT, it did not significantly alter endothelial cell viability or VEGF and TGFß mRNA expression. CONCLUSIONS: Findings of this study support the involvement of VEGF, TGFß, angiostatin, endostatin, and MMP-2 in the pathobiology of RIGT. However, the relationship between these mediators is complex and needs further investigation to improve understanding of their therapeutic potential in RIGT.

Radiotherapy-induced gut toxicity: Involvement of matrix metalloproteinases and the intestinal microvasculature.

Purpose To review the literature surrounding the involvement of the endothelium and matrix metalloproteinases (MMP) in radiotherapy-induced gut toxicity (RIGT) and further elucidate its complex pathobiology. Results RIGT involves damage to the gastrointestinal mucosa and is associated with diarrhoea, pain, and rectal bleeding depending on the area of exposure. The mechanisms underpinning RIGT are complex and have not yet been elucidated. Members of the MMP family, particularly MMP-2 and -9, have recently been identified as being key markers in RIGT and chemotherapy-induced gut toxicity (CIGT). Furthermore, the microvasculature has long been implicated in the development of toxicities following both chemotherapy and radiotherapy, however, the mechanisms behind this are yet to be explored. Conclusions It is proposed that matrix metalloproteinases are key regulators of endothelial mediators, and may play a key role in inducing damage to intestinal microvasculature following radiotherapy.

Matrix metalloproteinases and gut toxicity following cytotoxic cancer therapy.

PURPOSE OF REVIEW: Chemotherapy is an effective anticancer treatment; however, it induces mucositis in a wide range of patients. This condition is characterized by pain and ulceration, vomiting, bloating and diarrhea, depending on the area of the alimentary tract affected. Although treatment is available for a small subset of patients suffering from mucositis, the majority rely on pain relief as their only treatment option. Much progress has been made in recent years into understanding the pathobiology underlying the development of mucositis and matrix metalloproteinases (MMPs) have been implicated as being key mediators. The purpose of this review was to evaluate recent literature implicating MMPs in mucositis. RECENT FINDINGS: MMPs are well known for their roles in induction of inflammation and contribution to tissue injury. Recent literature provides a role for MMPs in mucositis development possibly through inflammatory pathways, alterations in extracellular matrix composition, adhesion molecules and tight junctions. SUMMARY: Better understanding of the precise roles of MMPs is now required in order to target appropriate treatment strategies.

Gastrointestinal mucositis: the role of MMP-tight junction interactions in tissue injury.

Chemotherapy for cancer causes significant gut toxicity known as mucositis. The pathogenesis of mucositis is ill defined. Recent clinical research guidelines have highlighted epithelial junctional complexes as emerging targets within mucositis research. Given the robust biological evidence linking tight junctions and matrix metalloproteinases, key mediators of mucositis, tight junction proteins have received significant attention. Despite this, the link between tight junctions, matrix metalloproteinases and mucositis development is yet to be established. This critical review therefore aims to describe the role of matrix metalloproteinases in mucositis, and how matrix metalloproteinase-dependent tight junction disruption may contribute to the pathobiology of mucositis.

Irinotecan disrupts tight junction proteins within the gut : implications for chemotherapy-induced gut toxicity.

Chemotherapy for cancer causes significant gut toxicity, leading to severe clinical manifestations and an increased economic burden. Despite much research, many of the underlying mechanisms remain poorly understood hindering effective treatment options. Recently there has been renewed interest in the role tight junctions play in the pathogenesis of chemotherapy-induced gut toxicity. To delineate the underlying mechanisms of chemotherapy-induced gut toxicity, this study aimed to quantify the molecular changes in key tight junction proteins, ZO-1, claudin-1, and occludin, using a well-established preclinical model of gut toxicity. Female tumor-bearing dark agouti rats received irinotecan or vehicle control and were assessed for validated parameters of gut toxicity including diarrhea and weight loss. Rats were killed at 6, 24, 48, 72, 96, and 120 h post-chemotherapy. Tight junction protein and mRNA expression in the small and large intestines were assessed using semi-quantitative immunohistochemistry and RT-PCR. Significant changes in protein expression of tight junction proteins were seen in both the jejunum and colon, correlating with key histological changes and clinical features. mRNA levels of claudin-1 were significantly decreased early after irinotecan in the small and large intestines. ZO-1 and occludin mRNA levels remained stable across the time-course of gut toxicity. Findings strongly suggest irinotecan causes tight junction defects which lead to mucosal barrier dysfunction and the development of diarrhea. Detailed research is now warranted to investigate posttranslational regulation of tight junction proteins to delineate the underlying pathophysiology of gut toxicity and identify future therapeutic targets.

Matrix metalloproteinases are possible mediators for the development of alimentary tract mucositis in the dark agouti rat.

Alimentary tract (AT) mucositis is a serious and debilitating side-effect of cancer therapy primarily characterized by damage of the mucous membranes throughout the AT. It is well established that this damage is a result of up-regulation of stress response genes and pro-inflammatory cytokines. Matrix metalloproteinases (MMPs) have been shown to function in several of the pathways known to be up-regulated in mucositis and play a key role in tissue injury and inflammation in many gastrointestinal disorders. This study aims to characterize the expression of multiple MMPs including MMP-1, -2, -3, -9 and -12 and their inhibitors, tissue inhibitor of metalloproteinase (TIMP)-1 and -2, in a rat model of irinotecan-induced mucositis. Dark agouti rats were administered a single 200 mg/kg intraperitoneal dose of irinotecan and killed at 1, 6, 24, 48, 72, 96 and 144 h following treatment. Hematoxylin and eosin staining, immunohistochemistry and realtime polymerase chain reaction were used to assess histopathological damage and MMP expression in the jejunum and colon. Marked histopathological evidence of mucositis was observed in the jejunum and colon as early as six hours following irinotecan treatment. A significant alteration in both gene expression and tissue levels of MMPs and TIMPs was noted following irinotecan. The increase in MMP-2, -3, -9 and -12 levels was associated with inflammatory infiltrate and maximum tissue damage. In contrast, MMP-1 expression correlated with tissue restitution. TIMP-1 and -2 levels were significantly altered in the jejunum following irinotecan. The augmentation in the expression profiles of MMPs and their inhibitors correlated with histopathological alterations observed in the tissue following irinotecan. This prompts the consideration of MMPs as possible mediators of chemotherapy-induced mucositis.

Matrix metalloproteinases: key regulators in the pathogenesis of chemotherapy-induced mucositis?

Chemotherapy is an effective anticancer treatment; however, it induces mucositis in a wide range of patients. Mucositis is the term used to describe the damage caused by radiation and chemotherapy to mucous membranes of the alimentary tract. This damage causes pain and ulceration, vomiting, bloating and diarrhoea, depending on the area of the alimentary tract affected. Although treatment is available for a small subset of patients suffering from mucositis, the majority rely on pain relief as their only treatment option. Much progress has been made in recent years into understanding the pathobiology underlying the development of mucositis. It is well established that chemotherapy causes prominent small intestinal and colonic damage as a result of up-regulation of stress response genes and pro-inflammatory cytokines. However, better understanding of the mediators of this damage is still required in order to target appropriate treatment strategies. Possible mediators of mucositis which have not been well researched are the matrix metalloproteinases (MMPs). MMPs have been shown to function in several of the pathways which are known to be up-regulated in mucositis and contribute to tissue injury and inflammation in many pathological conditions. This prompts the consideration of MMPs as possibly being key mediators in mucositis development.

HER2 targeted therapies for cancer and the gastrointestinal tract.

HER2 (v-erb-b2 erythroblastic leukemia viral oncogene) is a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. Since the discovery of a role for HER2 and other EGF receptors in the development and progression of cancer, they have become targets for a number of targeted anti-cancer drugs. These drugs have proven to be effective in treating and managing a range of cancers, however, recent observations in the clinic have suggested that their administration causes many toxicities, including gastrointestinal toxicity. Drugs with HER2 inhibitory activity fall into two categories; the monoclonal antibodies and small molecule tyrosine kinase inhibitors. Both of these drug classes have been shown to induce symptoms consistent with mucositis development; including nausea and vomiting, diarrhoea and abdominal pain. However, to date, limited studies have been carried out to justify the source of these toxicities. This review summarizes our current knowledge of the toxicities associated with commonly used HER2 targeted therapy drugs, the role of HER2 in cancer and the healthy gastrointestinal tract and the possible mechanisms by which drugs with HER2 inhibitory activity can induce gastrointestinal damage and possibly mucositis in patients.