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Hesse J, Müller T, Relógio A. An integrative mathematical model for timing treatment toxicity and Zeitgeber impact in colorectal cancer cells. NPJ Syst Biol Appl 2023; 9:27. [PMID: 37353516 DOI: 10.1038/s41540-023-00287-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 06/05/2023] [Indexed: 06/25/2023] Open
Abstract
Increasing evidence points to a role of the circadian clock in the regulation of cancer hallmarks with a strong impact on the understanding and treatment of this disease. Anti-cancer treatment can be personalized considering treatment timing. Here we present a new mathematical model based on data from three colorectal cancer cell lines and core-clock knock-outs, which couples the circadian and drug metabolism network, and that allows to determine toxicity profiles for a given drug and cell type. Moreover, this model integrates external Zeitgebers and thus may be used to fine-tune toxicity by using external factors, such as light, and therefore, to a certain extent, help fitting the endogenous rhythms of the patients to a defined clinic routine facilitating the implementation of time-dependent treatment in clinical practice.
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Affiliation(s)
- Janina Hesse
- Institute for Systems Medicine, Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, 20457, Germany
| | - Tim Müller
- Institute for Theoretical Biology (ITB), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, 10117, Germany
| | - Angela Relógio
- Institute for Systems Medicine, Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, 20457, Germany.
- Institute for Theoretical Biology (ITB), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, 10117, Germany.
- Molecular Cancer Research Center (MKFZ), Medical Department of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, 10117, Germany.
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2
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Abstract
Chemotherapy-induced gastrointestinal dysfunction is a common occurrence associated with many different classes of chemotherapeutic agents. Gastrointestinal toxicity includes mucositis, diarrhea, and constipation, and can often be a dose-limiting complication, induce cessation of treatment and could be life threatening. The gastrointestinal epithelium is rich in rapidly dividing cells and hence is a prime target for chemotherapeutic drugs. The incidence of gastrointestinal toxicity, including diarrhea and mucositis, is extremely high for a wide array of chemotherapeutic and radiation regimens. In fact, 60%-100% of patients on high-dose chemotherapy suffer from gastrointestinal side effects. Unfortunately, treatment options are limited, and therapy is often restricted to palliative care. Therefore, there is a great unmet therapeutic need for preventing and treating chemotherapy-induced gastrointestinal toxicities in the clinic. In this review, we discuss our current understanding of the mechanisms underlying chemotherapy-induced diarrhea and mucositis, and emerging mechanisms involving the enteric nervous system, smooth muscle cells and enteric immune cells. Recent evidence has also implicated gut dysbiosis in the pathogenesis of not only chemotherapy-induced mucositis and diarrhea, but also chemotherapy-induced peripheral neuropathy. Oxidative stress induced by chemotherapeutic agents results in post-translational modification of ion channels altering neuronal excitability. Thus, investigating how chemotherapy-induced changes in the gut- microbiome axis may lead to gut-related toxicities will be critical in the discovery of new drug targets for mitigating adverse gastrointestinal effects associated with chemotherapy treatment.
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Affiliation(s)
- Hamid I Akbarali
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States.
| | - Karan H Muchhala
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Donald K Jessup
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Stanley Cheatham
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
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Singh KP, Dhruva A, Flowers E, Paul SM, Hammer MJ, Wright F, Cartwright F, Conley YP, Melisko M, Levine JD, Miaskowski C, Kober KM. Alterations in Patterns of Gene Expression and Perturbed Pathways in the Gut-Brain Axis Are Associated With Chemotherapy-Induced Nausea. J Pain Symptom Manage 2020; 59:1248-1259.e5. [PMID: 31923555 PMCID: PMC7239734 DOI: 10.1016/j.jpainsymman.2019.12.352] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 12/10/2019] [Accepted: 12/11/2019] [Indexed: 12/12/2022]
Abstract
CONTEXT Despite current advances in antiemetic treatments, approximately 50% of oncology patients experience chemotherapy-induced nausea (CIN). OBJECTIVES The purpose of this study was to evaluate for differentially expressed genes and perturbed pathways associated with the gut-brain axis (GBA) across two independent samples of oncology patients who did and did not experience CIN. METHODS Oncology patients (n = 735) completed study questionnaires in the week before their second or third cycle of chemotherapy. CIN occurrence was assessed using the Memorial Symptom Assessment Scale. Gene expression analyses were performed in two independent samples using ribonucleic acid sequencing (Sample 1, n = 357) and microarray (Sample 2, n = 352) methodologies. Fisher's combined probability method was used to determine genes that were differentially expressed and pathways that were perturbed between the two nausea groups across both samples. RESULTS CIN was reported by 63.6% of the patients in Sample 1 and 48.9% of the patients in Sample 2. Across the two samples, 703 genes were differentially expressed, and 37 pathways were found to be perturbed between the two CIN groups. We identified nine perturbed pathways that are involved in mechanisms associated with alterations in the GBA (i.e., mucosal inflammation, disruption of gut microbiome). CONCLUSION Persistent CIN remains a significant clinical problem. Our study is the first to identify novel GBA-related pathways associated with the occurrence of CIN. Our findings warrant confirmation and suggest directions for future clinical studies to decrease CIN occurrence.
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Affiliation(s)
- Komal P Singh
- School of Nursing, University of California, San Francisco, San Francisco, California, USA
| | - Anand Dhruva
- School of Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Elena Flowers
- School of Nursing, University of California, San Francisco, San Francisco, California, USA
| | - Steven M Paul
- School of Nursing, University of California, San Francisco, San Francisco, California, USA
| | - Marilyn J Hammer
- The Phyllis F. Cantor Center for Research in Nursing and Patient Care Services, Dana Farber Cancer Institute, Boston, Massachusetts, USA
| | - Fay Wright
- Rory Meyers College of Nursing, New York University, New York, New York, USA
| | - Frances Cartwright
- Department of Nursing, Mount Sinai Medical Center, New York, New York, USA
| | - Yvette P Conley
- School of Nursing, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Michelle Melisko
- School of Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Jon D Levine
- School of Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Christine Miaskowski
- School of Nursing, University of California, San Francisco, San Francisco, California, USA
| | - Kord M Kober
- School of Nursing, University of California, San Francisco, San Francisco, California, USA.
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Thorpe D, Butler R, Sultani M, Vanhoecke B, Stringer A. Irinotecan-Induced Mucositis Is Associated with Goblet Cell Dysregulation and Neural Cell Damage in a Tumour Bearing DA Rat Model. Pathol Oncol Res 2019; 26:955-965. [PMID: 30919275 DOI: 10.1007/s12253-019-00644-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 03/19/2019] [Indexed: 01/02/2023]
Abstract
Irinotecan-induced mucositis is a major oncological problem. Goblet cells secrete mucus, protecting the intestinal mucosa, with secretion altered during mucositis. The enteric nervous system is involved in regulating gut motility and secretion. The aim of this study was to determine whether enteric neural cells and goblet cells are altered following irinotecan treatment. Tumour-bearing Dark Agouti rats were administered a single dose of 175 mg/kg of irinotecan intraperitoneally and 0.01 mg/kg atropine subcutaneously. Experimental and untreated control rats were killed at times 6, 24, 48, 72, 96 and 120 h after treatment. Jejunum and colon samples were formalin fixed. Haematoxylin and eosin staining, Alcian Blue-PAS staining, and immunohistochemistry with S-100 antibody (neural cell marker) were carried out. Statistical analyses were carried out using Kruskal-Wallis test with Dunns post test, Mann Whitney U test and nonlinear regression. Total goblet cells decreased at 72 h compared with controls in the colon (p < 0.05). The percentage of cavitated goblet cells decreased compared to all other time points at 120 h in the colon. The number of S-100 positive cells in the submucosal plexus decreased in the colon (p = 0.0046) and in the myenteric plexus of the jejunum and colon (p = 0.0058 and p = 0.0022, respectively), when comparing treated with control. Enteric ganglia in the myenteric plexus of the jejunum decreased at 24 h and 96 h. Irinotecan-induced mucositis is associated with increases in mucus secretion, and enteric neural cell change. These changes may contribute to the pathophysiology of mucositis through the dysregulation of neural signalling.
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Affiliation(s)
- Daniel Thorpe
- School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, 5001, Australia.
| | - Ross Butler
- School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, 5001, Australia
| | - Masooma Sultani
- School of Medical Sciences, Adelaide University, South Australia, Adelaide, 5001, Australia
| | - Barbara Vanhoecke
- Center for Microbiology Ecology and Technology, University of Ghent, Ghent, Belgium
| | - Andrea Stringer
- School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, 5001, Australia
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Thorpe D, Sultani M, Stringer A. Irinotecan induces enterocyte cell death and changes to muc2 and muc4 composition during mucositis in a tumour-bearing DA rat model. Cancer Chemother Pharmacol 2019; 83:893-904. [PMID: 30815720 DOI: 10.1007/s00280-019-03787-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 01/29/2019] [Indexed: 11/25/2022]
Abstract
Irinotecan-induced mucositis is a major oncological problem. Goblet cells secrete mucus, protecting the intestinal mucosa, with secretion altered during mucositis. The enteric nervous system is involved in regulating gut motility and secretion. The aim of this study was to determine whether enteric neural cells and goblet cells are altered following irinotecan treatment. Tumour-bearing Dark Agouti rats were administered a single dose of 175 mg/kg of irinotecan intraperitoneally and 0.01 mg/kg atropine subcutaneously. Experimental and untreated control rats were killed at times 6, 24, 48, 72, 96 and 120 h after treatment. Jejunum and colon samples were formalin fixed. Haematoxylin and eosin staining, Alcian Blue-PAS staining, and immunohistochemistry with S-100 antibody (neural cell marker) were carried out. Statistical analyses were carried out using Kruskal-Wallis test with Dunns post test, Mann Whitney U test, and nonlinear regression. Total goblet cells decreased at 72 h compared with controls in the colon (p < 0.05). The percentage of cavitated goblet cells decreased compared to all other time points at 120 h in the colon. The number of S-100-positive cells in the submucosal plexus decreased in the colon (p = 0.0046) and in the myenteric plexus of the jejunum and colon (p = 0.0058 and p = 0.0022, respectively), on comparing treated with control. Enteric ganglia in the myenteric plexus of the jejunum decreased at 24 h and 96 h. Irinotecan-induced mucositis is associated with increases in mucus secretion and enteric neural cell change. These changes may contribute to the pathophysiology of mucositis through the dysregulation of neural signalling.
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Affiliation(s)
- Daniel Thorpe
- School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, 5001, Australia.
| | - Masooma Sultani
- School of Medical Sciences, Adelaide University, Adelaide, 5001, Australia
| | - Andrea Stringer
- School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, 5001, Australia
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Chen XX, Lam KH, Chen QX, Leung GPH, Tang SCW, Sze SCW, Xiao JB, Feng F, Wang Y, Zhang KYB, Zhang ZJ. Ficus virens proanthocyanidins induced apoptosis in breast cancer cells concomitantly ameliorated 5-fluorouracil induced intestinal mucositis in rats. Food Chem Toxicol 2017; 110:49-61. [PMID: 29030256 DOI: 10.1016/j.fct.2017.10.017] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2017] [Revised: 10/07/2017] [Accepted: 10/09/2017] [Indexed: 02/08/2023]
Abstract
5-Fluorouracil (5-FU) is a commonly used chemotherapeutic agent for breast cancer. However, its use often leads to drug resistance and mucositis. This study aimed to investigate whether proanthocyanidins from Ficus virens possessed anti-breast cancer and anti-mucositis activities. The results showed that the cytotoxic effects of the proanthocyanidins against MDA-MB-231 and MCF-7 breast cancer cells were in the order of stem barks proanthocyanidins (SPAs) > leaves proanthocyanidins > fruits proanthocyanidins. Moreover, SPAs induced apoptosis in both cell lines which were accompanied with an increase in loss of mitochondrial membrane potential, production of reactive oxygen species, Bax to Bcl-2 protein expression ratio, and activated caspase 3. Furthermore, intraperitoneal injection of 5-FU (150 mg/kg body weight) resulted in body weight loss and jejunal injury in the rats while administration of SPAs (100 mg/kg body weight) counteracted these changes. Collectively, our study demonstrated that SPAs induced apoptosis cell death in breast cancer cells while ameliorating the symptoms of intestinal mucositis in rats.Therefore, SPAs merits further exploration as a potential therapeutic agent for breast cancer and chemotherapy-induced mucositis.
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Affiliation(s)
- Xiao-Xin Chen
- School of Chinese Medicine, LKS Faculty of Medicine, University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong
| | - Kar Ho Lam
- School of Chinese Medicine, LKS Faculty of Medicine, University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong
| | - Qing-Xi Chen
- Key Lab of the Ministry of Education for Coastal and Wetland Ecosystems, School of Life Sciences, Xiamen University, Xiamen, China
| | - George Pak-Heng Leung
- Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong
| | - Sydney Chi Wai Tang
- Department of Medicine, LKS Faculty of Medicine, University of Hong Kong, 102 Pokfulam Road, Hong Kong
| | - Stephen Cho-Wing Sze
- School of Chinese Medicine, LKS Faculty of Medicine, University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong
| | - Jian-Bo Xiao
- Institute of Chinese Medical Sciences, University of Macau (UM).N22 Research Building, Avenida da Universidade, Taipa, Macau, China
| | - Feng Feng
- Department of Natural Products Chemistry, Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Road, Jiangning, China
| | - Ying Wang
- Department of Histopathology, Sichuan Cancer Hospital, 55 Tongzi Lin Road, Chengdu, Sichuan, China
| | - Kalin Yan-Bo Zhang
- School of Chinese Medicine, LKS Faculty of Medicine, University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong.
| | - Zhang-Jin Zhang
- School of Chinese Medicine, LKS Faculty of Medicine, University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong.
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Marcussen M, Skrubbeltrang C, Bødker JS, Christiansen I, Bøgsted M, Dybkær K, Bergmann OJ, Johnsen HE. A systematic review of molecular responses to cancer therapy in normal human mucosa. Oral Surg Oral Med Oral Pathol Oral Radiol 2017; 124:355-366. [PMID: 29042035 DOI: 10.1016/j.oooo.2017.08.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2017] [Revised: 07/24/2017] [Accepted: 08/01/2017] [Indexed: 01/19/2023]
Abstract
OBJECTIVE Cancer therapy-induced inflammation of oral and gastrointestinal mucosae affects patients nonuniformly. Preventive strategies are limited; no biomarker exists for pretreatment identification of patients likely to be severely affected. Animal models are preferred for studying molecular responses in mucosae during chemotherapy, but translation into clinical practice is difficult. We performed a systematic review to retrieve articles that described molecular changes in human mucosae during cancer therapy. STUDY DESIGN We searched MEDLINE and Ovid Embase searches for studies reported in the English language literature from January 1990 to November 2016 and studies referenced in selected articles, which analyzed mucosae from patients at risk of developing mucositis during cancer therapy. Two authors extracted data according to predefined data fields, including study quality indicators. RESULTS We identified 17 human studies on chemotherapy (n = 9) and radiotherapy (n = 8), but no studies on targeted therapy. Studies were heterogeneous with regard to patient cohorts, analysis methods, cancer treatments, biopsy timings, and correlations to clinical mucositis. Consequently, a meta-analysis was not feasible. CONCLUSIONS Few human studies described the molecular responses of the normal mucosa to cancer therapy. Studies were heterogeneous and had sparse correlations to clinical mucositis. We proposed a model for acquiring data on treatment- and disease-specific phenotypes and transcriptomes for predictive or preventive initiatives.
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Affiliation(s)
- Mette Marcussen
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
| | | | - Julie Støve Bødker
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
| | - Ilse Christiansen
- Department of Haematology, Aalborg University Hospital, Aalborg, Denmark
| | - Martin Bøgsted
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark; Department of Haematology, Aalborg University Hospital, Aalborg, Denmark
| | - Karen Dybkær
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark; Department of Haematology, Aalborg University Hospital, Aalborg, Denmark
| | - Olav Jonas Bergmann
- School of Dentistry, Faculty of Health Science, Aarhus University; Aarhus, Denmark
| | - Hans Erik Johnsen
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark; Department of Haematology, Aalborg University Hospital, Aalborg, Denmark
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8
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Kuchay RAH. A review of complementary therapies for chemotherapy induced gastrointestinal mucositis. Drug Discov Ther 2017; 10:292-299. [PMID: 27746417 DOI: 10.5582/ddt.2016.01059] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Administration of chemotherapy often leads to gastrointestinal mucositis (GIM). GIM manifests as nausea, abdominal pain and diarrhoea in recipients of chemotherapy. GIM is a major complication occurring in approximately 80% of patients receiving 5-flurouracil treatment. These side-effects may become so severe that significant dose reductions are required, ultimately affecting treatment efficacy and patient survival. Complementary and alternative medicine (CAM) is a growing area of public interest. This review will provide an overview of current knowledge of complementary medicinal therapies for chemotherapy induced GIM. An understanding of this evolving literature is useful in discussing these therapies with patients who are considering using them.
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Mayo BJ, Stringer AM, Bowen JM, Bateman EH, Keefe DM. Irinotecan-induced mucositis: the interactions and potential role of GLP-2 analogues. Cancer Chemother Pharmacol 2016; 79:233-249. [PMID: 27770239 DOI: 10.1007/s00280-016-3165-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 10/06/2016] [Indexed: 12/11/2022]
Abstract
PURPOSE A common side effect of irinotecan administration is gastrointestinal mucositis, often manifesting as severe diarrhoea. The damage to the structure and function of the gastrointestinal tract caused by this cytotoxic agent is debilitating and often leads to alterations in patients' regimens, hospitalisation or stoppage of treatment. The purpose of this review is to identify mechanisms of irinotecan-induced intestinal damage and a potential role for GLP-2 analogues for intervention. METHODS This is a review of current literature on irinotecan-induced mucositis and GLP-2 analogues mechanisms of action. RESULTS Recent studies have found alterations that appear to be crucial in the development of severe intestinal mucositis, including early apoptosis, alterations in proliferation and cell survival pathways, as well as induction of inflammatory cascades. Several studies have indicated a possible role for glucagon-like peptide-2 analogues in treating this toxicity, due to its proven intestinotrophic, anti-apoptotic and anti-inflammatory effects in other models of gastrointestinal disease. CONCLUSION This review provides evidence as to why and how this treatment may improve mucositis through the possible molecular crosstalk that may be occurring in models of severe intestinal mucositis.
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Affiliation(s)
- Bronwen J Mayo
- School of Medicine, University of Adelaide, Adelaide, South Australia, Australia. .,School of Pharmacy and Medical Sciences, Sansom Institute for Health Sciences, University of South Australia, Adelaide, South Australia, Australia.
| | - Andrea M Stringer
- School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.,School of Pharmacy and Medical Sciences, Sansom Institute for Health Sciences, University of South Australia, Adelaide, South Australia, Australia
| | - Joanne M Bowen
- School of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Emma H Bateman
- School of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Dorothy M Keefe
- School of Medicine, University of Adelaide, Adelaide, South Australia, Australia
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Abstract
PURPOSE OF REVIEW Microbiota secrete a multitude of factors that either confer virulence or promote colonization because they are continuously challenged by host immune responses. The dynamic interplay between the host's immune response and microbiota eventually determines the outcome for the host: health or disease. Toll-like receptors (TLRs) play a key role in this interplay as they can recognize both microbial and host-derived ligands on the basis of the context in which recognition occurs. RECENT FINDINGS Evidence is accumulating that conventional cancer therapies alter interactions and cross talks between the host and microbiota. This has been shown for intestinal mucositis, a common side-effect of various cancer therapies. Advances have been made in the development of new and less toxic cancer strategies. One promising field is immunotherapy on the basis of TLR activation through recognition of microbial-associated molecular patterns. SUMMARY Evidence is emerging, indicating that existing cancer therapies have implications on the composition and functionality of the host-microbiota environment. This may favor the colonization of pathogens and build up the overall toxicity of the drug. Exploitation of the host-microbiota cross talks mediated by TLRs is an emerging and promising field in the search for new, less toxic anticancer strategies.
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Vanhoecke B, Bateman E, Mayo B, Vanlancker E, Stringer A, Thorpe D, Keefe D. Dark Agouti rat model of chemotherapy-induced mucositis: establishment and current state of the art. Exp Biol Med (Maywood) 2015; 240:725-41. [PMID: 25966981 PMCID: PMC4935219 DOI: 10.1177/1535370215581309] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Mucositis is a major oncological problem. The entire gastrointestinal and genitourinary tract and also other mucosal surfaces can be affected in recipients of radiotherapy, and/or chemotherapy. Major progress has been made in recent years in understanding the mechanisms of oral and small intestinal mucositis, which appears to be more prominent than colonic damage. This progress is largely due to the development of representative laboratory animal models of mucositis. This review focuses on the development and establishment of the Dark Agouti rat mammary adenocarcinoma model by the Mucositis Research Group of the University of Adelaide over the past 20 years to characterize the mechanisms underlying methotrexate-, 5-fluorouracil-, and irinotecan-induced mucositis. It also aims to summarize the results from studies using different animal model systems to identify new molecular and cellular markers of mucositis.
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Affiliation(s)
- Barbara Vanhoecke
- Mucositis Research Group, Centre for Personalised Cancer Medicine (CPCM), Centre for Clinical Research Excellence (CCRE) in Oral Health, Faculty of Health Sciences, University of Adelaide, Adelaide, 5005 South Australia, Australia Laboratory of Microbial Ecology and Technology, University of Ghent, 9000 Ghent, Belgium
| | - Emma Bateman
- Mucositis Research Group, Centre for Personalised Cancer Medicine (CPCM), Centre for Clinical Research Excellence (CCRE) in Oral Health, Faculty of Health Sciences, University of Adelaide, Adelaide, 5005 South Australia, Australia
| | - Bronwen Mayo
- Mucositis Research Group, Centre for Personalised Cancer Medicine (CPCM), Centre for Clinical Research Excellence (CCRE) in Oral Health, Faculty of Health Sciences, University of Adelaide, Adelaide, 5005 South Australia, Australia Sansom Institute for Health Research, University of South Australia, Adelaide, 5001 South Australia, Australia
| | - Eline Vanlancker
- Laboratory of Microbial Ecology and Technology, University of Ghent, 9000 Ghent, Belgium
| | - Andrea Stringer
- Sansom Institute for Health Research, University of South Australia, Adelaide, 5001 South Australia, Australia
| | - Daniel Thorpe
- Sansom Institute for Health Research, University of South Australia, Adelaide, 5001 South Australia, Australia
| | - Dorothy Keefe
- Mucositis Research Group, Centre for Personalised Cancer Medicine (CPCM), Centre for Clinical Research Excellence (CCRE) in Oral Health, Faculty of Health Sciences, University of Adelaide, Adelaide, 5005 South Australia, Australia Director, SA Cancer Service, Royal Adelaide Hospital, Adelaide, 5005 South Australia, Australia
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12
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Lee CS, Ryan EJ, Doherty GA. Gastro-intestinal toxicity of chemotherapeutics in colorectal cancer: The role of inflammation. World J Gastroenterol 2014; 20:3751-3761. [PMID: 24744571 PMCID: PMC3983434 DOI: 10.3748/wjg.v20.i14.3751] [Citation(s) in RCA: 153] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Accepted: 02/27/2014] [Indexed: 02/06/2023] Open
Abstract
Chemotherapy-induced diarrhea (CID) is a common and often severe side effect experienced by colorectal cancer (CRC) patients during their treatment. As chemotherapy regimens evolve to include more efficacious agents, CID is increasingly becoming a major cause of dose limiting toxicity and merits further investigation. Inflammation is a key factor behind gastrointestinal (GI) toxicity of chemotherapy. Different chemotherapeutic agents activate a diverse range of pro-inflammatory pathways culminating in distinct histopathological changes in the small intestine and colonic mucosa. Here we review the current understanding of the mechanisms behind GI toxicity and the mucositis associated with systemic treatment of CRC. Insights into the inflammatory response activated during this process gained from various models of GI toxicity are discussed. The inflammatory processes contributing to the GI toxicity of chemotherapeutic agents are increasingly being recognised as having an important role in the development of anti-tumor immunity, thus conferring added benefit against tumor recurrence and improving patient survival. We review the basic mechanisms involved in the promotion of immunogenic cell death and its relevance in the treatment of colorectal cancer. Finally, the impact of CID on patient outcomes and therapeutic strategies to prevent or minimise the effect of GI toxicity and mucositis are discussed.
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13
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Stringer AM, Logan RM. The role of oral flora in the development of chemotherapy-induced oral mucositis. J Oral Pathol Med 2014; 44:81-7. [DOI: 10.1111/jop.12152] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/05/2013] [Indexed: 12/21/2022]
Affiliation(s)
- Andrea M. Stringer
- School of Pharmacy and Medical Sciences; University of South Australia; Adelaide SA Australia
- School of Medical Sciences; The University of Adelaide; Adelaide SA Australia
| | - Richard M. Logan
- School of Dentistry; Faculty of Health Sciences; The University of Adelaide; Adelaide SA Australia
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14
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Cheah KY, Howarth GS, Bastian SEP. Grape seed extract dose-responsively decreases disease severity in a rat model of mucositis; concomitantly enhancing chemotherapeutic effectiveness in colon cancer cells. PLoS One 2014; 9:e85184. [PMID: 24465501 PMCID: PMC3897410 DOI: 10.1371/journal.pone.0085184] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Accepted: 12/03/2013] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE Mucositis is a serious disorder of the gastrointestinal tract that results from cancer chemotherapy. We investigated the effects of increasing grape seed extract doses on the severity of chemotherapy in a rat model and its coincident impact on chemotherapeutic effectiveness in colon cancer cells. DESIGN Female Dark Agouti rats were gavaged with grape seed extract (400-1000 mg/kg) or water (day 3-11) and were injected intraperitoneally with 5-Fluorouracil (150 mg/kg) or saline (control) on day 9 to induce mucositis. Daily metabolic data were collected and rats were sacrificed on day 12. Intestinal tissues were collected for histological and myeloperoxidase analyses. Caco-2 cell viability was examined in response to grape seed extract in combination with 5-Fluorouracil by 3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide) assay. RESULTS Compared with 5-Fluorouracil controls, grape seed extract (400-1000 mg/kg) significantly decreased the histological damage score (P<0.05) in the jejunum. Grape seed extract (1000 mg/kg) increased jejunal crypt depth by 25% (P<0.05) in 5-Fluorouracil treated rats compared to 5-Fluorouracil controls, and attenuated the 5-Fluorouracil -induced reduction of mucosal thickness (25%, P<0.05). Grape seed extract (600 mg/kg) decreased myeloperoxidase activity by 55% (P<0.01) compared to 5-Fluorouracil controls. Grape seed extract was more effective at ameliorating 5-Fluorouracil induced intestinal injury, with effects most pronounced in the proximal jejunum. Grape seed extract (10-25 ug/mL) significantly enhanced the growth-inhibitory effects of 5-Fluorouracil by 26% (P<0.05) in Caco-2 cells and was more potent than 5-Fluorouracil at 50-100 µg/mL. CONCLUSION Grape seed extract may represent a new therapeutic option to decrease the symptoms of intestinal mucositis while concurrently impacting on the viability of colon cancer cells.
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Affiliation(s)
- Ker Yeaw Cheah
- School of Agriculture, Food and Wine, Waite Campus, University of Adelaide, South Australia, Australia
- Centre for Paediatric and Adolescent Gastroenterology, Children, Youth and Women's Health Service, North Adelaide, South Australia, Australia
| | - Gordon Stanley Howarth
- Centre for Paediatric and Adolescent Gastroenterology, Children, Youth and Women's Health Service, North Adelaide, South Australia, Australia
- School of Animal and Veterinary Sciences, Roseworthy Campus, University of Adelaide, South Australia, Australia
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Thorpe D, Stringer A, Butler R. Chemotherapy-induced mucositis: The role of mucin secretion and regulation, and the enteric nervous system. Neurotoxicology 2013; 38:101-5. [DOI: 10.1016/j.neuro.2013.06.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Revised: 06/13/2013] [Accepted: 06/23/2013] [Indexed: 01/19/2023]
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16
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Stringer AM, Al-Dasooqi N, Bowen JM, Tan TH, Radzuan M, Logan RM, Mayo B, Keefe DMK, Gibson RJ. Biomarkers of chemotherapy-induced diarrhoea: a clinical study of intestinal microbiome alterations, inflammation and circulating matrix metalloproteinases. Support Care Cancer 2013; 21:1843-52. [PMID: 23397098 DOI: 10.1007/s00520-013-1741-7] [Citation(s) in RCA: 101] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Accepted: 01/29/2013] [Indexed: 10/27/2022]
Abstract
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-1β 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-1β 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-1β 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-1β 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.
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Affiliation(s)
- Andrea M Stringer
- School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
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17
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Thorpe DW, Stringer AM, Gibson RJ. Chemotherapy-induced mucositis: the role of the gastrointestinal microbiome and toll-like receptors. Exp Biol Med (Maywood) 2013; 238:1-6. [PMID: 23479757 DOI: 10.1258/ebm.2012.012260] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Alimentary mucositis is a major clinical problem. Patients with mucositis are at significantly increased risk of infection and are often hospitalized for prolonged periods. More importantly, these patients often have to undergo reductions in their cytotoxic therapy, which may lead to reduced survival. Unfortunately, there are very limited therapeutic options for mucositis and no effective prevention. The human gut microbiome is receiving increased attention as a key player in the pathogenesis of alimentary mucositis with recent literature suggesting that changes in bacteria lead to mucositis. The bacteria which are found throughout the gut are tightly regulated by the toll-like receptor (TLR) family which currently has 13 known members. TLRs play a critical role in gut homeostasis and bacterial regulation. Furthermore, TLRs play a critical role in the regulation of nuclear factor kappa B, a key regulator of alimentary mucositis. However to date, no research has clearly identified a link between TLRs and alimentary mucositis. This critical literature review seeks to correct this.
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Affiliation(s)
- Daniel W Thorpe
- School of Pharmacy and Medical Sciences, University of South Australia, North Terrace, Adelaide 5000, South Australia, Australia
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18
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Interaction between host cells and microbes in chemotherapy-induced mucositis. Nutrients 2013; 5:1488-99. [PMID: 23628721 PMCID: PMC3708331 DOI: 10.3390/nu5051488] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Revised: 04/05/2013] [Accepted: 04/07/2013] [Indexed: 02/07/2023] Open
Abstract
Cancer patients receiving chemotherapy often develop mucositis as a direct result of their treatment. Recently, the intestinal microbiota has attracted significant attention in the investigation of the pathobiology of mucositis, with a number of studies investigating the effects of chemotherapeutic agents on the microbiota. With significant effects on the intestinal microbiota occurring following the administration of chemotherapy, there is now interest surrounding the downstream pathological effects that may be associated with the altered intestinal ecology. This review seeks to identify links between signalling pathways previously demonstrated to have a role in the development of mucositis, and the altered intestinal microbiota.
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Anti-inflammatory cytokines: important immunoregulatory factors contributing to chemotherapy-induced gastrointestinal mucositis. CHEMOTHERAPY RESEARCH AND PRACTICE 2012; 2012:490804. [PMID: 22973511 PMCID: PMC3437608 DOI: 10.1155/2012/490804] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2012] [Revised: 07/25/2012] [Accepted: 07/25/2012] [Indexed: 12/13/2022]
Abstract
“Mucositis” is the clinical term used to describe ulceration and damage of the mucous membranes of the entire gastrointestinal tract (GIT) following cytotoxic cancer chemotherapy and radiation therapy common symptoms include abdominal pain, bloating, diarrhoea, vomiting, and constipation resulting in both a significant clinical and financial burden. Chemotherapeutic drugs cause upregulation of stress response genes including NFκB, that in turn upregulate the production of proinflammatory cytokines such as interleukin-1β (IL-1β), Interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α). These proinflammatory cytokines are responsible for initiating inflammation in response to tissue injury. Anti-inflammatory cytokines and specific cytokine inhibitors are also released to limit the sustained or excessive inflammatory reactions. In the past decade, intensive research has determined the role of proinflammatory cytokines in development of mucositis. However, a large gap remains in the knowledge of the role of anti-inflammatory cytokines in the setting of chemotherapy-induced mucositis. This critical paper will highlight current literature available relating to what is known regarding the development of mucositis, including the molecular mechanisms involved in inducing inflammation particularly with respect to the role of proinflammatory cytokines, as well as provide a detailed discussion of why it is essential to consider extensive research in the role of anti-inflammatory cytokines in chemotherapy-induced mucositis so that effective targeted treatment strategies can be developed.
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Ahowesso C, Li XM, Zampera S, Peteri-Brunbäck B, Dulong S, Beau J, Hossard V, Filipski E, Delaunay F, Claustrat B, Lévi F. Sex and dosing-time dependencies in irinotecan-induced circadian disruption. Chronobiol Int 2011; 28:458-70. [PMID: 21721861 DOI: 10.3109/07420528.2011.569043] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Circadian disruption accelerates malignant growth; thus, it should be avoided in anticancer therapy. The circadian disruptive effects of irinotecan, a topoisomerase I inhibitor, was investigated according to dosing time and sex. In previous work, irinotecan achieved best tolerability following dosing at zeitgeber time (ZT) 11 in male and ZT15 in female mice, whereas worst toxicity corresponded to treatment at ZT23 and ZT3 in male and female mice, respectively. Here, irinotecan (50 mg/kg intravenous [i.v.]) was delivered at the sex-specific optimal or worst circadian timing in male and female B6D2F1 mice. Circadian disruption was assessed with rest-activity, body temperature, plasma corticosterone, and liver mRNA expressions of clock genes Rev-erbα, Per2, and Bmal1. Baseline circadian rhythms in rest-activity, body temperature, and plasma corticosterone were more prominent in females as compared to males. Severe circadian disruption was documented for all physiology and molecular clock endpoints in female mice treated at the ZT of worst tolerability. Conversely, irinotecan administration at the ZT of best tolerability induced slight alteration of circadian physiology and clock-gene expression patterns in female mice. In male mice, irinotecan produced moderate alterations of circadian physiology and clock-gene expression patterns, irrespective of treatment ZT. However, the average expression of Rev-erbα, Per2, and Bmal1 were down-regulated 2- to 10-fold with irinotecan at the worst ZT, while being minimally or unaffected at the best ZT, irrespective of sex. Corticosterone secretion increased acutely within 2 h with a sex-specific response pattern, resulting in a ZT-dependent phase-advance or -delay in both sex. The mRNA expressions of irinotecan clock-controlled metabolism genes Ce2, Ugt1a1, and Top1 were unchanged or down-regulated according to irinotecan timing and sex. This study shows that the circadian timing system represents an important toxicity target of irinotecan in female mice, where circadian disruption persists after wrongly timed treatment. As a result, the mechanisms underling cancer chronotherapeutics are expectedly more susceptible to disruption in females as compared to males. Thus, the optimal circadian timing of chemotherapy requires precise determination according to sex, and should involve the noninvasive monitoring of circadian biomarkers.
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Affiliation(s)
- Constance Ahowesso
- INSERM, UMRS 776 Rythmes biologique et cancers, Hôpital Paul Brousse, Villejuif, France
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21
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Xue H, Sawyer MB, Wischmeyer PE, Baracos VE. Nutrition modulation of gastrointestinal toxicity related to cancer chemotherapy: from preclinical findings to clinical strategy. JPEN J Parenter Enteral Nutr 2011; 35:74-90. [PMID: 21224434 DOI: 10.1177/0148607110377338] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Chemotherapy-induced gut toxicity is a major dose-limiting toxicity for many anticancer drugs. Gastrointestinal (GI) complications compromise the efficacy of chemotherapy, promote overall malnutrition, aggravate cancer cachexia, and may contribute to worsened prognosis. The GI tract is an attractive target for nutrition modulation, owing to its direct exposure to the diet, participation in uptake and metabolism of nutrients, high rate of cell turnover, and plasticity to nutrition stimuli. Glutamine, ω-3 polyunsaturated fatty acids, and probiotics/prebiotics are therapeutic factors that potentially modulate GI toxicity related to cancer treatments. Preclinical and clinical evidence are reviewed to critically define plausible benefits of these factors and their potential development into adjuncts to cancer chemotherapy. Mechanisms underlying the action of these nutrients are being unraveled in the laboratory. Optimal strategies to translate these findings into clinical care still remain to be elucidated. Key questions that remain to be answered include the following: which nutrient or combination of nutrients is selected for which patient and chemotherapy regimen? What mechanisms are responsible for modulation, and how are nutrient(s) administered in a clinically optimal manner? Research exploring interactions between different nutrients in GI protection is ongoing and demands further understanding. How nutrition preparations given to chemotherapy-treated patients are formulated in terms of component selection and dose optimization should be carefully studied and justified.
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Affiliation(s)
- Hongyu Xue
- Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
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Al-Dasooqi N, Bowen JM, Gibson RJ, Logan RM, Stringer AM, Keefe DM. Selection of housekeeping genes for gene expression studies in a rat model of irinotecan-induced mucositis. Chemotherapy 2011; 57:43-53. [PMID: 21282945 DOI: 10.1159/000321477] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2010] [Accepted: 07/13/2010] [Indexed: 11/19/2022]
Abstract
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/β-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/β-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.
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Affiliation(s)
- Noor Al-Dasooqi
- Department of Medicine, University of Adelaide, Adelaide, S.A., Australia.
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23
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Al-Dasooqi N, Gibson RJ, Bowen JM, Logan RM, Stringer AM, Keefe DM. Matrix metalloproteinases are possible mediators for the development of alimentary tract mucositis in the dark agouti rat. Exp Biol Med (Maywood) 2010; 235:1244-56. [PMID: 20682600 DOI: 10.1258/ebm.2010.010082] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
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.
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Affiliation(s)
- Noor Al-Dasooqi
- Department of Medicine, University of Adelaide, North Terrace, Adelaide, SA 5005, Australia.
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Bowen JM, Tsykin A, Stringer AM, Logan RM, Gibson RJ, Keefe DMK. Kinetics and regional specificity of irinotecan-induced gene expression in the gastrointestinal tract. Toxicology 2010; 269:1-12. [PMID: 20097248 DOI: 10.1016/j.tox.2009.12.020] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2009] [Revised: 12/18/2009] [Accepted: 12/21/2009] [Indexed: 12/31/2022]
Abstract
Gastrointestinal toxicity remains a significant and dose-limiting complication of cancer treatment. While the pathophysiology is becoming clearer, considerable gaps in the knowledge remain surrounding the timing and site-specific gene changes which occur in response to insult. As such, this study aimed to assess gene expression profiles in a number of regions along the gastrointestinal tract following treatment with the chemotherapy agent, irinotecan, and correlate them with markers of cell death and tissue damage. Data analysis of microarray results found that genes involved in apoptosis, mitogen activated kinase (MAPK) signalling and inflammation were upregulated within 6h, while genes involved in cell proliferation, wound healing and blood vessel formation were upregulated at later time points up to 72 h. Cell death was significantly increased at 6 and 24h, and the stomach showed the lowest severity of overt tissue damage. Real time PCR of MAPK signalling pathway genes found that the jejunum and colon had significantly increased expression in a number of genes at 72 h, where as the stomach was unchanged. These results indicate that overall severity of tissue damage may be determined by precisely timed target gene responses specific to each region. Therapeutic targeting of key gene responses at the appropriate time point may prove to be effective for prevention of chemotherapy-induced gastrointestinal damage.
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25
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Technological advances in mucositis research: new insights and new issues. Cancer Treat Rev 2008; 34:476-82. [PMID: 18358615 DOI: 10.1016/j.ctrv.2008.02.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2007] [Revised: 02/05/2008] [Accepted: 02/07/2008] [Indexed: 02/06/2023]
Abstract
The last decade has seen a significant acceleration in the introduction of molecular tools used in cancer diagnosis and treatment. Driving factors have been the movement of advanced technologies from the laboratory to the clinic and the shift to a more genetically individualised patient approach. With this has followed an increased ability to study the toxic side effects of cancer treatment, some of which are newly emerging, by utilising many of the same technologies. Mucositis research in particular has reached a golden period of investigation and understanding of the pathobiological mechanisms that contribute to the development of the condition. This paper has selected a few of the emerging technologies that are highly relevant to mucositis research to discuss in detail. These technologies include target therapies, toxicogenomics, nanomedicine, pharmacogenetics and pharmacogenomics, with a particular focus on microarray technology. These technologies are critical to discuss in the context of mucositis research not only because they are widely applicable to cutting edge research, but they also provide opportunities for further advances both in the laboratory and clinical setting. In addition, some of these technologies have the potential to be implemented immediately in the field of mucositis research.
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Xanthinaki A, Nicolatou-Galitis O, Athanassiadou P, Gonidi M, Kouloulias V, Sotiropoulou-Lontou A, Pissakas G, Kyprianou K, Kouvaris J, Patsouris E. Apoptotic and inflammation markers in oral mucositis in head and neck cancer patients receiving radiotherapy: preliminary report. Support Care Cancer 2008; 16:1025-33. [PMID: 18197435 DOI: 10.1007/s00520-007-0379-8] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2007] [Accepted: 12/06/2007] [Indexed: 11/28/2022]
Abstract
GOAL OF WORK The aim of this study was to investigate the expression of pro-apoptotic protein p53 and anti-apoptotic proteins BCl-2 and MCl-1, as well as the expression of pro-inflammatory cytokines tumor necrosis factor (TNF) and interleukin-1beta (IL-1beta) in patients developing mucositis during radiotherapy for head and neck cancer. MATERIALS AND METHODS Thirty-five patients receiving radiotherapy for head/neck cancer were included in this study. Patients were examined before radiotherapy. Oral mucositis was recorded weekly during radiotherapy. Cytologic smears from the oral cavity were taken with a brush. Immunocytochemical staining was performed by the use of p53, BCl-2, MCl-1 TNF and IL-1beta monoclonal antibodies. MAIN RESULTS P53 was expressed in 1 of 15 smears before the initiation of radiotherapy (6.5%) compared to 3 of 7 smears from patients with grade III mucositis (43%) during radiotherapy. BCl-2 was expressed in 15 of 15 smears before radiotherapy (100%) and in three of seven patients with grade III mucositis (43%) during radiotherapy. MCl-1 was expressed in 10 of 14 samples before radiotherapy (71.5%) and in two of seven patients with grade III (28.5%) mucositis during radiotherapy. TNF was expressed in 9 of 14 patients before radiotherapy (64%) and in six of seven patients with grade III mucositis during radiotherapy (86%). IL-1beta was detected in 7 of 14 patients before radiotherapy (50%) compared to 6 of 7 patients with grade III mucositis during radiotherapy (86%). CONCLUSION Our preliminary results indicate an induction of apoptosis and inflammation in the oral mucosa in patients developing mucositis during radiotherapy for head/neck cancer.
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Affiliation(s)
- Arsinoi Xanthinaki
- Dental Oncology Unit, Clinic of Hospital Dentistry, School of Dentistry, University of Athens, Athens, Greece.
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Bowen JM, Gibson RJ, Tsykin A, Stringer AM, Logan RM, Keefe DMK. Gene expression analysis of multiple gastrointestinal regions reveals activation of common cell regulatory pathways following cytotoxic chemotherapy. Int J Cancer 2007; 121:1847-56. [PMID: 17594691 DOI: 10.1002/ijc.22895] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Gastrointestinal mucositis involves many changes at the gene level, affecting epithelial/subepithelial interactions and leading to overt damage. The regional specificity and time course of these changes, and how they relate to subsequent mucositis development however remain unknown. The aim of this study was to determine the early time course of gene expression changes along the gastrointestinal tract of the DA rat following chemotherapy. Female DA rats were treated with a single dose of 200 mg/kg irinotecan to induce mucositis, and were killed at short intervals following treatment. Small sections of stomach, jejunum and colon were harvested for analysis of genetic profiles. RNA was hybridised to high density Affymetrix oligonucleotide microarrays. Data analysis was carried out with software package, TimeCourse, freely available through Bioconductor. As early as 1 hr following chemotherapy, expression of hundreds of genes was altered, including those for transcription factors, stress response proteins and protein turnover. These genes are involved in cell proliferation, differentiation and apoptosis along with other cellular processes. At early time points, there was a significant response involving the mitogen-activated protein kinase pathway, cell cycle regulation and cytokine receptor signalling. At later time points, changes to the complement cascade became prominent. We have shown that changes in gene expression following chemotherapy occur by 1 hr, and persist for at least 72 hr after treatment. Many of these changes are highly likely to be specifically related to the subsequent development of gastrointestinal mucositis.
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Affiliation(s)
- Joanne M Bowen
- Department of Medical Oncology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia.
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Yeoh ASJ, Gibson RJ, Yeoh EEK, Bowen JM, Stringer AM, Giam KA, Keefe DMK. A novel animal model to investigate fractionated radiotherapy-induced alimentary mucositis: the role of apoptosis, p53, nuclear factor-kappaB, COX-1, and COX-2. Mol Cancer Ther 2007; 6:2319-27. [PMID: 17699727 DOI: 10.1158/1535-7163.mct-07-0113] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Radiation-induced mucositis is a common and serious side effect of radiotherapy. Molecular mechanisms of mucosal injury, however, are still poorly understood and extremely difficult to study in humans. A novel Dark Agouti rat model using fractionated radiotherapy to induce mucositis has been developed to investigate the occurrence of alimentary mucosal injury. Twenty-four Dark Agouti rats were randomly assigned to receive either fractionated radiotherapy or no radiotherapy. The irradiated rats received a fractionated course of abdominal radiotherapy at 45 Gy/18 fractions/6 weeks treating thrice weekly (i.e., at a radiation dose of 2.5 Gy per fraction). After each week of radiation, a group of irradiated rats was killed. Histomorphology and mucin distribution in the alimentary tract was investigated. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was used to examine apoptosis in the colon and jejunum, and intestinal morphometry was used to assess villus length, crypt length, and mitotic crypt count. Immunohistochemistry of p53, nuclear factor-kappaB, cyclooxygenase (COX)-1, and COX-2 was also done. The fractionated radiotherapy course induced alimentary mucositis from week 1, with more severe injury seen in the small intestine. The hallmark appearance of apoptosis was present in the crypts of the small and large intestine. In the jejunum and colon, goblet cell disorganization and degeneration was obvious and crypt mitotic counts were severely depleted throughout the treatment. Expression of p53, nuclear factor-kappaB, COX-1, and COX-2 was increased in the irradiated intestinal sections. Fractionated radiation-induced alimentary mucositis has been effectively documented in the Dark Agouti rat for the first time. Further studies investigating the molecular mechanisms underlying radiation-induced mucositis are planned to ultimately achieve anti-mucotoxic-targeted therapies.
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Affiliation(s)
- Ann S J Yeoh
- Department of Medical Oncology, Royal Adelaide Hospital, South Australia, Australia.
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Logan RM, Stringer AM, Bowen JM, Yeoh ASJ, Gibson RJ, Sonis ST, Keefe DMK. The role of pro-inflammatory cytokines in cancer treatment-induced alimentary tract mucositis: pathobiology, animal models and cytotoxic drugs. Cancer Treat Rev 2007; 33:448-60. [PMID: 17507164 DOI: 10.1016/j.ctrv.2007.03.001] [Citation(s) in RCA: 203] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2007] [Revised: 03/23/2007] [Accepted: 03/27/2007] [Indexed: 12/14/2022]
Abstract
Alimentary tract (AT) mucositis can be a major problem for patients undergoing cancer treatment. It has significant clinical and economic consequences and is a major factor that can compromise the provision of optimal treatment for patients. The pathobiology of AT mucositis is complex and the exact mechanisms that underlie its development still need to be fully elucidated. Current opinion considers that there is a prominent interplay between all of the compartments of the mucosa involving, at a molecular level, the activation of transcription factors, particularly nuclear factor-kappaB, and the subsequent upregulation of pro-inflammatory cytokines and inflammatory mediators. The purpose of this review is to examine the literature relating to what is currently known about the pathobiology of AT mucositis, particularly with respect to the involvement of pro-inflammatory cytokines, as well as currently used animal models and the role of specific cytotoxic chemotherapy agents in the development of AT mucositis.
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Affiliation(s)
- Richard M Logan
- Oral Pathology, School of Dentistry, Faculty of Health Sciences, The University of Adelaide, North Terrace, Adelaide SA 5005, Australia.
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Supportive care silos: time to forge cross-links, using mucositis as an example. Curr Opin Support Palliat Care 2007; 1:40-2. [DOI: 10.1097/spc.0b013e32814e6bd3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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