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Hindawi Publishing Corporation Journal of Oncology Volume 2008, Article ID 907892, 7 pages doi:10.1155/2008/907892 Review Article 1, 2, 3 1, 2 Joanne M. Bowen and Dorothy M. K. Keefe Department of Medical Oncology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia Division of Medicine, The University of Adelaide, Adelaide, SA 5000, Australia Mucositis Research Laboratory, Hanson Institute, Frome Rd, Adelaide, South Australia 5000, Australia Correspondence should be addressed to Joanne M. Bowen, firstname.lastname@example.org Received 19 June 2008; Accepted 12 August 2008 Recommended by James Mulshine Alimentary mucositis is a major dose-limiting toxicity associated with anticancer treatment. It is responsible for reducing patient quality of life and represents a signiﬁcant economic burden in oncology. The pathobiology of alimentary mucositis is extremely complex, and an increased understanding of mechanisms and pathway interactions is required to rationally design improved therapies. This review describes the latest advances in deﬁning mechanisms of alimentary mucositis pathobiology in the context of pathway activation. It focuses particularly on the recent genome-wide analyses of regimen-related mucosal injury and the identiﬁcation of speciﬁc regulatory pathways implicated in mucositis development. This review also discusses the currently known alimentary mucositis risk factors and the development of novel treatments. Suggestions for future research directions have been raised. Copyright © 2008 J. M. Bowen and D. M. K. Keefe. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 1. Introduction 40% in patients undergoing standard chemotherapy for solid tumours, up to 60–100% in those undergoing high dose Recent research has indicated that cytotoxic chemotherapy conditioning chemotherapy for stem cell transplantation causes unwanted normal tissue damage via its eﬀects on a [5, 8]. multitude of cellular regulatory pathways [1, 2]. In particular, investigations have begun to elucidate the role of regula- 2. Burden of Alimentary Mucositis tory pathway activation and suppression in regimen-related gastrointestinal toxicity [2, 3]. Mucosal toxicity following anticancer treatment is clinically referred to as mucositis. Alimentary mucositis represents a signiﬁcant clinical and Mucositis was once separated into oral and gastrointestinal, economic burden in oncology. The presence of any mucositis however it is now widely known as alimentary mucositis, during a cycle of chemotherapy signiﬁcantly increases the referring to the damage which occurs along the entire risk of dose reduction, the frequency of infections and orodigestive tract. Alimentary mucositis aﬀects the mucosa, bleeding, and increases the length and cost of hospitalisation. causing mouth and throat pain, ulceration, abdominal pain, Reduction in treatment doses leads to reduced survival , bloating, vomiting, and diarrhoea depending on the target and mucositis is also a risk factor for mortality due to tissue [4–6]. The general mechanisms underpinning the its association with infection . What is more, severe development of mucositis are thought to be the same mucositis has been shown to be a signiﬁcant risk factor for regardless of the location along the length of the tract. inferior overall survival, relapse mortality, and nonrelapse However, the kinetics of symptom development is diﬀerent mortality in speciﬁc settings . Resource utilisation for in each region, which is thought to reﬂect the local turnover patients during episodes of mucositis is also signiﬁcantly rate of epithelial cells and specialised diﬀerentiation for local increased, with the need for nutritional adjuncts including function [4, 7]. The frequency of alimentary mucositis varies ﬂuid replacement, liquid diets, and total parenteral nutrition. depending on the cancer and treatment, ranging from 10– Due to the association with infection, antibiotic therapy is 2 Journal of Oncology also more common in patients with mucositis. Combined, are similar along the entire length of the alimentary canal. this translates to an incremental cost increase of US$3500 In models of mucositis, inﬂammatory mediators, TNF per cycle of standard dose chemotherapy with oral mucositis and NFkB, have been shown to increase along the length [12, 13] and US$6000 with both oral and GI mucositis . of the gastrointestinal tract corresponding to histological While the full burden of mucositis has yet to be deﬁned, a damage [27, 28]. Furthermore, proinﬂammatory cytokines, prospective study is ongoing to determine its true quality of interleukin 1 and 6, are increased following methotrexate life and economic impact. treatment and associated with a loss of gut barrier function . Disruption of these signalling pathways ameliorates intestinal mucositis. Treatment with NFkB inhibitors has 3. Current Overview Mucositis Pathobiology been shown to partially prevent mucosal injury in an Accumulating evidence has strengthened the proposed bio- animal model of anticancer treatment . Another anti- logical model of mucositis [15, 16]. It is known as the inﬂammatory agent under development, RDP58, signiﬁ- multiple mechanism model, as it represents a divergence cantly inhibited intestinal damage induced by irinotecan from the initial linear view that mucositis was purely a result through its ability to prevent treatment-related increases of cytotoxic agent-induced damage to basal epithelial cells in TNF, Interferon-γ, and interleukin-12 . Research is [17, 18]. There is indeed interference with epithelial stem ongoing to fully elucidate the mechanisms of gastrointestinal cell turnover and increased apoptosis following anticancer mucositis. Loss of crypt stem cells remains an important treatment, however this is but one component of the event in intestinal injury following anticancer treatment. pathobiology of alimentary mucositis. Rather, the events However, it is not the sole contributing factor leading to overt damage. The inﬂammatory cascade is being realised that lead to mucosal injury are multifactorial, complex, and pan tissue and are driven initially by the submucosa as an important pathway in the development of intestinal via endothelial signalling [16, 19]. Epithelial breakdown mucositis that can be pharmacologically manipulated. represents the clinical stage only and is associated with loss of barrier integrity, host infection, and considerable pain 5. Overview of Current Understanding of [4, 7, 20–22]. Mucositis has been described as having 5 Risk Factors for Mucosal Toxicity phases, which are overlapping and interactive [16, 22]. The 5 phases are initiation, primary damage response/upregulation and message generation, signal ampliﬁcation, ulceration, and Mucosal susceptibility is based on global and tissue-speciﬁc healing. Brieﬂy, cytotoxic agents initiate damage through factors. Global components are associated with treatment the generation of reactive oxygen species which causes both and patient characteristics, while tissue speciﬁc components direct damage to tissue components of the mucosa and also are related to epithelial type, the intrinsic endocrine system, activates secondary signalling. The primary event of the and the local microbial environment . The choice of message generation phase centres around activation of the drug, the schedule, and dose-intensity of the regimen will transcription factor NFkB, which leads to the upregulation impact on the risk of toxicity . Patient related variables of many genes involved in perpetuating mucosal injury, include gender, ethnicity, and presence of comorbidities such including proinﬂammatory cytokines, adhesion molecules, as diabetes mellitus , although the absolute association and cyclooxygenase-2. During the third phase, a feedback is far less clear for these variables compared to treatment. loop occurs whereby the proinﬂammatory cytokine, TNF, Cellular and molecular elements that inﬂuence toxicity will acts on a number of pathways to reinforce NFkB activation depend on the local tissue environment, in which mucosal and the ceramide pathway. The ulcerative phase comprises responses to damaging stimuli, whether direct or indirect loss of mucosal integrity and bacterial colonisation, with through intermediate mediators, are contingent on the subsequent further proinﬂammatory cytokine production. particular location of the tissue and epithelial type, microbial Alimentary mucositis is usually self-resolving once treatment environment and speciﬁc regional functions . ceases, and healing occurs with renewal of epithelial prolifer- While the interactions between global and tissue speciﬁc ation and diﬀerentiation and reestablishment of the normal factors impact on mucosal injury, there are also underlying local microbial ﬂora [16, 23, 24]. It is evident that this current genetic inﬂuences that profoundly aﬀect toxicity. The genetic model incorporates sequential interaction between all cell component for predisposition to mucositis is well established and tissue types of the mucosa and submucosa, as well as [34, 35]. A classic proof of principle example is the ﬁnding tissue factors, cytokines, and elements of the luminal envi- from clinical trials that genetic susceptibility to apoptosis ronment [25, 26]. Among others, the pathways implicated in can impact on the risk of mucositis. Patients with Addison’s this model include ceramide signalling, extracellular matrix disease, a condition characterised by excess apoptosis, are turnover, oxidative stress signalling, apoptosis, cytokine 17% more likely to develop oral mucositis during anticancer signalling, and cell cycling. treatment, and patients with Psoriasis, a condition of reduced apoptosis especially in skin, are 77% less likely to suﬀer oral mucositis [15, 16]. 4. Special Considerations for the GIT Although this is an elegant example, the most widely Mucositis pathobiology has been extrapolated mainly from accepted evidence for the genetic basis of mucositis risk is research in the oral setting. However there is rapidly accu- the observation that patients deﬁcient in drug-metabolising mulating evidence that supports the theory that mechanisms enzymes are at a higher risk of treatment toxicity . Journal of Oncology 3 Genetic Table 1: Genetically controlled elements that may directly or indi- predisposition rectly inﬂuence alimentary mucositis risk. Generic Tissue speciﬁc Tissue speciﬁc Drug metabolism, targets and transport Trefoils Mucosal injury Global factors Transcription factors Adhesion factors factors risk factors Proinﬂammatory cytokines Defensins Mediators Secretins Toxicity clusters Diﬀerential response to Susceptibility to apoptosis and rate CT/RT Figure 1: Relationship of proposed contributors implicated in development of alimentary mucositis. Speciﬁc examples of these include deﬁciencies in UDP- implying that each is a risk factor for the other and may glucuronosyltransferase 1A1 (UGLT), methylenetetrahydro- represent a common underlying aetiology . This novel folate reductase (MTHFR), thymidylate synthase (TS), and work has provided the opportunity to gain a new insight dihydropyrimidine dehydrogenase (DYDP), during irinote- into the relationship of multiple regimen-related toxicities. can, methotrexate, and 5-FU treatment, respectively [34, Overall, it seems that deﬁning mucosal injury risk factors is as 36]. Reduced levels of these proteins can be caused by complex as the pathobiology. The major components include hereditable inactivating mutations in the gene promoter global, tissue speciﬁc, genetic and clustering factors, and region and result in accumulation and drug prolonged these are combined with cellular and molecular interactions exposure. Pharmacogenetics seems an attractive solution to between factors which ultimately determine the mucosal explain all mucotoxicity, however the proportion of patients response to chemotherapy treatment (Figure 1). with these enzyme deﬁciencies is greatly less than the number of patients that suﬀer toxicity [2, 32]. It has been suggested that genetic variants of mucositis mediators, rather than 6. New Alimentary Mucositis Pathway Research metabolism enzymes, may be associated with the majority of toxicity. One such mediator is TNF. Recent studies have The biological events which induce alimentary mucositis shown that TNF gene polymorphisms are associated with begin almost immediately following administration of radio- altered risk of toxicity following cancer treatment [37, 38]. therapy and chemotherapy [21, 41]. Inhibition of these Patients that are heterozygous for the TNF-308 promoter early molecular events may have a profound impact on polymorphism have increased TNF production and are at a the intensity of mucosal damage and as such represents an signiﬁcantly greater risk of toxicities following myloablative attractive focus for research. Applying genomic proﬁling to chemotherapy treatment. Patients had a 17-fold increased mucositis research to investigate global molecular changes risk of complications following treatment including those following treatment is an increasing area of interest that aﬀecting the oral mucosa, skin, and gut, which is a holds much promise. The ability to simultaneously inves- stronger association than traditional mucositis risk variables tigate thousands of genes and their response to treatment of gender, age, and treatment dose . Although these has enhanced our ability to deﬁne the mechanisms of initial ﬁndings are encouraging, the complexity of mucositis damage speciﬁc to each drug and the generic response means that there is a continuing challenge to discover of tissue to anticancer treatment. We can now hypoth- more polymorphisms within candidate genes predictive of esis that many genes are initially aﬀected by anticancer regimen-related mucosal damage. These types of studies treatment which may be either unique to each drug or provide accumulating evidence to suggest that a number of common to all drugs. However, these early genes must activate a smaller subset of downstream genes, involved in genetically controlled elements can determine the response of the mucosa to cancer treatment, and that these can be speciﬁc signalling pathways that are vital to propagating either generic or tissue speciﬁc (Table 1). the cascade towards clinically signiﬁcant mucosal dam- Finally, the most recent area of research involved in age. What is more, it is likely that a threshold of key deﬁning risk factors for mucositis is toxicity clustering. gene activation must be reached before damage becomes Symptom clustering has previously been applied to a range inevitable. of nonmalignant diseases, and to cancer symptoms, and Two recent studies have directed considerable eﬀort has proven useful for creating diagnostic criteria. However, towards investigating the gene expression changes and in the context of anticancer treatment-related toxicity, it is pathway activation responsible for alimentary mucositis in its infancy . The general principle is that a patient development [2, 3]. Firstly, Sonis et al. investigated the who has alimentary mucositis is likely to have a particular relationship between gene expression, canonical pathways, subset of other toxicities and vice versa. A recent paper and functional networks in peripheral blood monocytes used Bayesian analysis to identify linked toxicities  of patients who developed mucosal injury in response to and Markov networks to deﬁne clusters of toxicities  chemoradiation . This study combined Bayesian theory in colorectal cancer patients following treatment. It found with network analysis to deﬁne the canonical pathways that gastrointestinal toxicities clustered together strongly, most relevant to regimen-related toxicity. They prioritised 4 Journal of Oncology Table 2: The top 14 cellular and regulatory pathways deemed to be most relevant to mucosal injury from anticancer therapy. Rank Chemoradiation (Sonis, et al.) Irinotecan (Bowen, et al.) 1 Toll-like receptor signalling MAPK signalling 2 NF-kB signalling Cell cycle 3 B-cell receptor signalling Complement and coagulation cascades 4 PI3K/AKT signalling Gap junction 5 Cell cycle Calcium signalling 6 P38 MAPK signalling Apoptosis 7 Wnt/B-catenin signalling Leukocyte transendothelium migration 8 Glutamate receptor signalling VEGF signalling 9 Integrin signalling Cytokine-cytokine receptor interaction 10 VEGF signalling Neuroactive ligand-receptor interaction 11 IL-6 signalling Wnt signalling 12 Death receptor signalling B cell receptor signalling 13 SAPK/JNK signalling T cell receptor signalling 14 T-cell receptor signalling Focal adhesion 14 pathways derived from the Ingenuity Pathways Analysis 7. Fitting Treatments with Pathways Library (Table 2). The study by Bowen et al. investigated gene expression and pathway modulation in the gastroin- There are a growing number of new antimucotoxic agents testinal tract of rats following irinotecan treatment . They currently being clinically tested. Mostly these agents target analysed their gene list using web tool, Pathway Miner, at least one or a few pathways identiﬁed as associated which searches genes based on their associations with cellular with mucosal injury. However, recent research indicates and regulatory pathways and performs a statistical test that only the agents that modulate multiple pathways will to rank the most signiﬁcant pathways . They found be truly eﬀective at inhibiting damage. A recent Cochrane over 20 pathways from the KEGG database involved in Library review of interventions for preventing oral mucositis tissue injury following cytotoxic treatment (Table 2). In both found that of the 33 interventions studied twelve showed studies, Fisher’s exact test was applied to the data set to some evidence of a beneﬁt. Of these, two pharmaceutical determine the most signiﬁcant pathways associated with agents appear particularly promising, namely, Amifostine toxicity. Metabolic pathways were also highly represented in and Benzydamine . These agents have also been included pathway lists and included nitrogen metabolism, oxidative in the Updated Clinical Practice Guidelines for the Preven- phosphorylation, purine metabolism, prostaglandin and tion and Treatment of Mucositis . Amifostine is a free leukotriene metabolism, and glutathione metabolism but radical scavenger which exerts its eﬀects by reducing direct were not investigated further. Gene association networks are DNA damage and reducing upregulation of inﬂammatory an informative method for analysing pathway relationships pathways . It has recently been recommended for use in among genes that are coregulated and for analysing up or prevention of radiation-induced proctitis, however it has yet down-regulated pathways that contain many participating to be recommended for mucositis [44, 46]. Benzydamine is genes . recommended for the prevention of mucositis in radiation These papers are the ﬁrst to use a bioinformatics patients. It has anti-inﬂammatory, analgesic, anaesthetic and approach to deﬁne the pathways altered by anticancer treat- antimicrobial eﬀects, although its primary mode of action ment during alimentary mucositis development. Despite is thought to be through inhibition of proinﬂammatory the use of diﬀerent databases in the two studies, there is cytokines . Mucositis is essentially an inﬂammatory considerable overlap within the prioritised pathways named. condition [47, 48], and the results of the microarray The diﬀerence between sampling methods (peripheral blood studies conﬁrm this paradigm by identifying multiple sig- verses gastrointestinal whole tissue) makes the results even nalling pathways involved in inﬂammation. These include more interesting, as it shows that local tissue damage is also NFkB signalling, complement and coagulation cascades, represented systemically. This has important implications for toll-like receptor signalling, MAPK signalling, cytokine- future research. It is also vital that future studies direct eﬀorts cytokine receptor interaction, as well as others shown in towards determining which signalling pathways are true the table above. It seems that these two agents have the drivers of damage and which are passengers, altered without potential to signiﬁcantly ameliorate mucosal injury through causing a functional change at the tissue level. What is more, modulating a large number of regulatory pathways. Still, the kinetics of pathway activation needs to be determined to Palifermin (recombinant human KGF-1) remains the only elucidate which are altered early as damage initiators, which agent currently approved by the FDA for the prevention and are upregulated as a consequence of damage, and which of treatment of mucositis . It is biologically pleiotropic. those are crucial to healing. Each represents a separate target Its primary mode of action was initially thought to rely for intervention. on accelerating healing by its role as an epithelial mitogen Journal of Oncology 5 enhancing proliferation, migration, and diﬀerentiation of Finally, a critical point that should be addressed before mucosal epithelium. However, Palifermin has also been any pathway-targeted treatment can be developed is the shown to exhibit protective functions outside of its general need to deﬁne diﬀerences in modulation of pathways in expected role, including inhibition of epithelial cell apoptosis normal tissue that result in toxicity versus the desired eﬀect and DNA damage, upregulation of detoxifying enzymes, on tumour tissue. We must be careful not to interrupt the and downregulation of proinﬂammatory cytokines . It is intended purpose of chemotherapy, and therefore consider- likely that Palifermin does this through some of the pathways ation needs to be given to designing drugs that are either discussed. In addition to these drugs, pathway knowledge speciﬁcally targeted to the mucosal surface or that exploit could be broadly applied to the development and discovery features of the normal cell for drug uptake. of new agents eﬀective in preventing mucosal injury. 9. Conclusions 8. Future Directions for Research Alimentary mucositis research has entered the “omic” era. With this has come a new depth of understanding of the One of the major challenges in deﬁning the most appro- molecular and cellular interactions associated with devel- priate molecular targets for mucositis intervention is the opment of mucosal injury in response to cancer treatment. highly complex and interactive nature of its pathobiology. One of the most exciting outcomes of recent research It seems likely that the main approach to elucidating the has been the characterisation and prioritising of pathways polygenic determinants of treatment will be genomics, in implicated in mucositis pathobiology. In the future, this particular applying the use of anonymous single nucleotide piece of information will help to rationally design improved polymorphism (SNP) maps to perform a genome-wide drugs and provide early identiﬁcation of patients at risk of search for SNPs associated with treatment eﬀects [51, 52]. developing severe mucositis. This is opposed to the more traditional technique of singly investigating candidate genes based on existing knowledge References of a drug’s mechanism of action and the known pathways of metabolism and deposition [51, 52]. This “omic” direc-  R. S. Herbst, “Toxicities of antiangiogenic therapy in non- small-cell lung cancer,” Clinical Lung Cancer, vol. 8, supple- tion, coupled with powerful bioinformatics, should greatly ment 1, pp. S23–S30, 2006. advance our ability to unravel the complex network of  S. T. Sonis, R. Haddad, M. 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