Rachel J Gibson
Research interests
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InterestsHistopathology, Immunohistochemistry, Surgical Pathology, Molecular Pathology, Histopathological techniques, Anatomical Pathological Conditions, Clinical Pathology
Publications
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5.30Impact points
Biomarkers of regimen-related mucosal injury.
Cancer treatment reviews. 06/2011; 37(6):487-93.
Regimen-related mucosal toxicity is extremely common following cytotoxic chemotherapy and radiotherapy. The alimentary mucosa is particularly susceptible to injury and dysfunction, leading to a constellation of adverse side effects. Currently there is no "one fit" biomarker of such injury.... [more] Regimen-related mucosal toxicity is extremely common following cytotoxic chemotherapy and radiotherapy. The alimentary mucosa is particularly susceptible to injury and dysfunction, leading to a constellation of adverse side effects. Currently there is no "one fit" biomarker of such injury. A number of biomarkers have been investigated in the context of gastrointestinal diseases, which may prove useful in the oncology arena. Two of significant potential include citrulline and calprotectin, however more work is required to define the most appropriate settings for their use. Identification of a biomarker that is easily obtained, measured, and accurately indicates mucosal damage, would allow for improved patient diagnosis of toxicities and prompt appropriate intervention. In this review, we highlight the effectiveness of currently examined biomarkers and discuss future avenues for research in this exciting area.
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2.46Impact points
Irinotecan-induced alterations in intestinal cell kinetics and extracellular matrix component expression in the dark agouti rat.
International journal of experimental pathology. 04/2011; 92(5):357-65.
Chemotherapy-induced mucositis is characterized by damage of mucous membranes throughout the alimentary tract (AT). Extracellular matrix (ECM) components play a vital role in maintaining mucosal barrier integrity by regulating cellular apoptosis, proliferation and differentiation of overlying epithe... [more] Chemotherapy-induced mucositis is characterized by damage of mucous membranes throughout the alimentary tract (AT). Extracellular matrix (ECM) components play a vital role in maintaining mucosal barrier integrity by regulating cellular apoptosis, proliferation and differentiation of overlying epithelial cells. The aims of this study were to characterize the changes in epithelial cell kinetics and to investigate the expression of the ECM components in the gastrointestinal tract following irinotecan administration. Female dark agouti rats were treated with single 200 mg/kg dose irinotecan and killed at various time points (1, 6, 24, 48, 72, 96 and 14 h) after treatment. Ki67 immunostaining and TUNEL were used to assess proliferation and apoptosis, respectively, in the jejunum and colon. Masson trichrome staining and picro-sirius red staining were used to determine the level of collagen, and immunohistochemistry was used to further assess collagen IV, fibronectin and laminin 1 and 2 expression in these tissues. Irinotecan halved cellular proliferation in the jejunum and colon at 48 and 24 h, respectively, while apoptosis peaked at 6 h (P < 0.05). There was a substantial increase in total collagen deposits around crypts from 24 h in both regions. However, collagen IV expression decreased significantly in the crypt region in a delayed fashion (P < 0.05). Fibronectin expression decreased significantly in jejunum and colon from 6 to 24 h following treatment (P < 0.05). Irinotecan induced a significant alteration in epithelial cell kinetics in both the jejunum and colon, and this correlated with changes in ECM component expression. Changes in ECM expression may have a direct impact on the loss of mucosal layer integrity evident in chemotherapy-induced mucositis.
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2.03Impact points
Selection of housekeeping genes for gene expression studies in a rat model of irinotecan-induced mucositis.
Chemotherapy. 02/2011; 57(1):43-53.
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 valida... [more] 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. 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. 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. 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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2.64Impact points
Matrix metalloproteinases are possible mediators for the development of alimentary tract mucositis in the dark agouti rat.
Experimental biology and medicine (Maywood, N.J.). 10/2010; 235(10):1244-56.
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. Matri... [more] 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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2.53Impact points
Pro-inflammatory cytokines play a key role in the development of radiotherapy-induced gastrointestinal mucositis.
Radiation oncology (London, England). 03/2010; 5:22.
Mucositis is a toxic side effect of anti-cancer treatments and is a major focus in cancer research. Pro-inflammatory cytokines have previously been implicated in the pathophysiology of chemotherapy-induced gastrointestinal mucositis. However, whether they play a key role in the development of radiot... [more] Mucositis is a toxic side effect of anti-cancer treatments and is a major focus in cancer research. Pro-inflammatory cytokines have previously been implicated in the pathophysiology of chemotherapy-induced gastrointestinal mucositis. However, whether they play a key role in the development of radiotherapy-induced gastrointestinal mucositis is still unknown. Therefore, the aim of the present study was to characterise the expression of pro-inflammatory cytokines in the gastrointestinal tract using a rat model of fractionated radiotherapy-induced toxicity. Thirty six female Dark Agouti rats were randomly assigned into groups and received 2.5 Gys abdominal radiotherapy three times a week over six weeks. Real time PCR was conducted to determine the relative change in mRNA expression of pro-inflammatory cytokines IL-1beta, IL-6 and TNF in the jejunum and colon. Protein expression of IL-1beta, IL-6 and TNF in the intestinal epithelium was investigated using qualitative immunohistochemistry. Radiotherapy-induced sub-acute damage was associated with significantly upregulated IL-1beta, IL-6 and TNF mRNA levels in the jejunum and colon. The majority of pro-inflammatory cytokine protein expression in the jejunum and colon exhibited minimal change following fractionated radiotherapy. Pro-inflammatory cytokines play a key role in radiotherapy-induced gastrointestinal mucositis in the sub-acute onset setting.
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3.24Impact points
Kinetics and regional specificity of irinotecan-induced gene expression in the gastrointestinal tract.
Toxicology. 02/2010; 269(1):1-12.
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 ai... [more] 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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2.46Impact points
Irinotecan-induced mucositis manifesting as diarrhoea corresponds with an amended intestinal flora and mucin profile.
International journal of experimental pathology. 10/2009; 90(5):489-99.
Chemotherapy-induced diarrhoea is a major oncological problem, caused by the cytotoxic effects of cancer chemotherapy. Irinotecan is linked with severe mucositis and diarrhoea, the mechanisms of which remain poorly understood. Bacterial beta-glucuronidase is thought to be involved in the metabolism ... [more] Chemotherapy-induced diarrhoea is a major oncological problem, caused by the cytotoxic effects of cancer chemotherapy. Irinotecan is linked with severe mucositis and diarrhoea, the mechanisms of which remain poorly understood. Bacterial beta-glucuronidase is thought to be involved in the metabolism of irinotecan, implicating the intestinal flora. Intestinal mucins may also be implicated in the development of chemotherapy-induced diarrhoea. Rats were treated with 200 mg/kg of irinotecan and killed at 96, 120 and 144 h. The rats were monitored for diarrhoea. Pathology and immunohistochemical staining was performed. The samples were cultured and faecal DNA was analysed using real-time polymerase chain reaction. Severe diarrhoea was observed from 72 to 96 h. A decrease in body mass was also observed after treatment. Significant changes in goblet cell numbers (both complete and cavitated cells) were observed in the small and large intestines. Changes in MUC gene expression were observed in the small intestine only. Modifications were observed to the intestinal flora profile, especially Escherichia coli, and an increase in the expression of beta-glucuronidase was detected. In conclusion, irinotecan-induced diarrhoea may be caused by an increase in some beta-glucuronidase-producing bacteria, especially E. coli, exacerbating the toxicity of active metabolites. Accelerated mucous secretion and mucin release may also contribute to the delayed onset of diarrhoea.
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Chemotherapy-induced diarrhoea.
Current opinion in supportive and palliative care. 04/2009; 3(1):31-5.
PURPOSE OF REVIEW: Diarrhoea is a major manifestation of chemotherapy-induced mucositis that until recently has received very little attention. To date, there is no detailed understanding of the underlying mechanisms of the condition. The purpose of this review is to examine the plethora of recent s... [more] PURPOSE OF REVIEW: Diarrhoea is a major manifestation of chemotherapy-induced mucositis that until recently has received very little attention. To date, there is no detailed understanding of the underlying mechanisms of the condition. The purpose of this review is to examine the plethora of recent studies, both in the laboratory and in the clinic, which have attempted to elucidate effective treatment options. RECENT FINDINGS: Over recent years, there have been many new treatment options trialled for ameliorating chemotherapy-induced diarrhoea. Some of these have shown great promise in small clinical studies and now need to be investigated in larger trials. Furthermore, there have been developments in the understanding of the underlying mechanisms of chemotherapy-induced diarrhoea. These developments may also lead to effective treatment options. SUMMARY: Here, we describe the current thinking behind the mechanisms of chemotherapy-induced diarrhoea and present current and new treatment options. This opinion article highlights the shift towards more effective research into diarrhoea caused by chemotherapy.
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2.64Impact points
Gastrointestinal microflora and mucins may play a critical role in the development of 5-Fluorouracil-induced gastrointestinal mucositis.
Experimental biology and medicine (Maywood, N.J.). 01/2009;
5-Fluorouracil (5-FU) is a commonly used chemotherapy agent in clinical oncology practice. Two of its major side effects are mucositis and diarrhoea. The structure of mucins offers mucosal protection, and allows maintenance of intestinal flora by providing attachment sites and preventing bacterial o... [more] 5-Fluorouracil (5-FU) is a commonly used chemotherapy agent in clinical oncology practice. Two of its major side effects are mucositis and diarrhoea. The structure of mucins offers mucosal protection, and allows maintenance of intestinal flora by providing attachment sites and preventing bacterial overgrowth and/or penetration. The aim of this study was to investigate changes in mucin secretion and microflora following treatment with 5-FU. Female DA rats were given a single 150 mg/kg ip dose of 5-FU. Rats were killed at various time points after treatment. Control rats received no treatment. Jejunum, colon and faecal samples were collected. Standard microbiological culture techniques were used to identify bacteria, and real time PCR was used to quantify bacteria in faecal samples. Goblet cells and cavitated goblet cells (having undergone mucus exocytosis) were also counted. Statistical analysis was carried out using the Mann Whitney U-test, followed by Bonferroni correction. Following treatment with 5-FU, we showed decreases in Clostridium spp., Lactobacillus spp. and Streptococcus spp., and an increase in Escherichia spp. in the jejunum. In the colon, 5-FU caused decreases in Enterococcus spp., Lactobacillus spp. and Streptococcus spp. Real time PCR of faecal samples showed decreasing trends in Lactobacillus spp. and Bacteroides spp., and an increasing trend in E. coli. Significant increases (p<0.05) were seen in Clostridium spp. and Staphylococcus spp. at 24 h. Goblet cell numbers decreased significantly in the jejunum from 24-72 h, with a significant increase in the percentage of cavitated goblet cells. In conclusion, 5-FU treatment causes significant changes in intestinal flora and mucin secretion in rats. These changes could result in systemic effects, and in particular may contribute to the development of chemotherapy-induced mucositis.
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5.30Impact points
Technological advances in mucositis research: New insights and new issues.
Cancer treatment reviews. 09/2008; 34(5):476-82.
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. Wi... [more] 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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2.65Impact points
Characterisation of mucosal changes in the alimentary tract following administration of irinotecan: implications for the pathobiology of mucositis.
Cancer chemotherapy and pharmacology. 07/2008; 62(1):33-41.
PURPOSE: The pathobiology of alimentary tract (AT) mucositis is complex and there is limited information about the events which lead to the mucosal damage that occurs during cancer treatment. Various transcription factors and proinflammatory cytokines are thought to play important roles in pathogene... [more] PURPOSE: The pathobiology of alimentary tract (AT) mucositis is complex and there is limited information about the events which lead to the mucosal damage that occurs during cancer treatment. Various transcription factors and proinflammatory cytokines are thought to play important roles in pathogenesis of mucositis. The aim of this study was to determine the expression of nuclear factor-kappaB (NF-kappaB), tumor necrosis factor (TNF) and interleukins-1beta (IL-1beta) and -6 (IL-6) in the AT following the administration of the chemotherapeutic agent irinotecan. METHODS: Eighty-one female dark Agouti rats were assigned to either control or experimental groups according to a specific time point. Following administration of irinotecan, rats were monitored for the development of diarrhoea. The rats were killed at times ranging from 30 min to 72 h after administration of irinotecan. Oral mucosa, jejunum and colon were collected and standard immunohistochemical techniques were used to identify NF-kappaB, TNF, IL-1beta and IL-6 within the tissues. Sections were also stained with haematoxylin and eosin for histological examination. RESULTS: Irinotecan caused mild to moderate diarrhoea in a proportion of the rats that received the drug. Altered histological features of all tissues from rats administered irinotecan were observed which included epithelial atrophy in the oral mucosa, reduction of villus height and crypt length in the jejunum and a reduction in crypt length in the colon. Tissue staining for NF-kappaB, TNF and IL-1beta and IL-6 peaked at between 2 and 12 h in the tissues examined. CONCLUSIONS: This is the first study to demonstrate histological and immunohistochemical evidence of changes occurring concurrently in different sites of the AT following chemotherapy. The results of the study provide further evidence for the role of NF-kappaB and associated pro-inflammatory cytokines in the pathobiology of AT mucositis. The presence of these factors in tissues from different sites of the AT also suggests that there may be a common pathway along the entire AT causing mucositis following irinotecan administration.
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4.72Impact points
Gene expression analysis of multiple gastrointestinal regions reveals activation of common cell regulatory pathways following cytotoxic chemotherapy.
International journal of cancer. Journal international du cancer. 11/2007; 121(8):1847-56.
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 ... [more] 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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4.29Impact points
Severe mucositis: how can nutrition help?
Current opinion in clinical nutrition and metabolic care. 10/2007; 10(5):627-31.
PURPOSE OF REVIEW: To review the recent evidence on the effect of nutrition on the incidence and severity of mucositis following anticancer treatment. RECENT FINDINGS: There have been many recent publications on mucositis and on nutrition in cancer, but very few on nutrition and mucositis in cancer.... [more] PURPOSE OF REVIEW: To review the recent evidence on the effect of nutrition on the incidence and severity of mucositis following anticancer treatment. RECENT FINDINGS: There have been many recent publications on mucositis and on nutrition in cancer, but very few on nutrition and mucositis in cancer. It is difficult to establish a definite link between nutritional status, nutritional interventions and mucositis. Malnutrition is probably a risk factor for mucositis, however, and some of the interventions that improve nutrition in cancer patients and reduce the risk of cancer in the general population work via mechanisms that might positively affect the development and course of mucositis. Whilst it can be tempting to extrapolate these findings to suggest that nutritional support can reduce the incidence and severity of mucositis, this would be premature. SUMMARY: There may well be a link between nutritional status, nutritional supplementation, anticancer treatment and mucositis, but it is not yet proven; and mechanism-based, prospective, randomized studies are required to answer the question. This is likely to be an area of increased study in the future.
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2.71Impact points
VSL#3 probiotic treatment reduces chemotherapy-induced diarrhea and weight loss.
Cancer biology & therapy. 10/2007; 6(9):1449-54.
BACKGROUND: One of the most common toxicities of cancer treatment is diarrhea. Probiotics have been shown effective at preventing diarrhea in inflammatory bowel disease and may prove useful in the oncology setting. AIM: The primary aim of this study was to investigate the probiotic mixture, VSL#3, f... [more] BACKGROUND: One of the most common toxicities of cancer treatment is diarrhea. Probiotics have been shown effective at preventing diarrhea in inflammatory bowel disease and may prove useful in the oncology setting. AIM: The primary aim of this study was to investigate the probiotic mixture, VSL#3, for amelioration of chemotherapy-induced diarrhea (CID). METHODS: This experiment was carried out in a clinically relevant model of CID. VSL#3 was administered to female DA rats in one of three schedules. Irinotecan was used to induce mucositis and diarrhea, with rats monitored for seven days to record incidence of weight-loss and diarrhea. At study completion, intestines were collected to investigate histological and proliferative changes, apoptosis levels and mucin composition. Results: VSL#3 reduced weight loss following irinotecan when administered before and after chemotherapy. Moderate and severe diarrhea was also prevented in these rats. This was associated with a significant increase in crypt proliferation combined with an inhibition of apoptosis in both the small and large intestines. VSL#3 also prevented irinotecan-induced increases in goblet cells within jejunal crypts. CONCLUSIONS: VSL#3 is effective at preventing severe diarrhea following chemotherapy with irinotecan and therefore has potential to be used clinically by cancer patients.
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4.95Impact points
A novel animal model to investigate fractionated radiotherapy-induced alimentary mucositis: the role of apoptosis, p53, nuclear factor-kappaB, COX-1, and COX-2.
Molecular cancer therapeutics. 09/2007; 6(8):2319-27.
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 develop... [more] 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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5.30Impact points
The role of pro-inflammatory cytokines in cancer treatment-induced alimentary tract mucositis: pathobiology, animal models and cytotoxic drugs.
Cancer treatment reviews. 09/2007; 33(5):448-60.
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 ... [more] 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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Chemotherapy-induced mucositis: the role of gastrointestinal microflora and mucins in the luminal environment.
The journal of supportive oncology. 07/2007; 5(6):259-67.
Collectively, mucositis refers to the damage caused to the mucous membranes of the body following cytotoxic cancer therapy. Diarrhea is one such manifestation of mucositis and is a common side effect of chemotherapy that remains poorly understood. It affects the entire gastrointestinal tract. The ex... [more] Collectively, mucositis refers to the damage caused to the mucous membranes of the body following cytotoxic cancer therapy. Diarrhea is one such manifestation of mucositis and is a common side effect of chemotherapy that remains poorly understood. It affects the entire gastrointestinal tract. The exact number of patients affected by diarrhea as a result of treatment is uncertain, although it is believed that approximately 10% of patients with advanced cancer will be affected. Despite advances in the understanding of oral and small intestinal mucositis over recent years, large intestinal mucositis, including diarrhea, has not been well defined, and the underlying mechanisms of the condition have yet to be established. The majority of the literature concerning diarrhea is based on clinical observations, with little basic research. However, from the research conducted, it is likely that the intestinal microflora play a role in the development of chemotherapy-induced diarrhea. This review will examine in detail what is known about the mechanisms of chemotherapy-induced diarrhea and will explore the potentially important relationship among intestinal microflora, the luminal environment, and the subsequent development of chemotherapy-induced diarrhea.
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2.09Impact points
Mucosal injury from targeted anti-cancer therapy.
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 06/2007; 15(5):483-90.
BACKGROUND: With the increased use of so-called targeted anti-cancer therapies, there has been a change in toxicities that patients are experiencing. As most targeted therapies are given in conjunction with more traditional chemotherapeutic agents, toxicities of these combination therapies are also ... [more] BACKGROUND: With the increased use of so-called targeted anti-cancer therapies, there has been a change in toxicities that patients are experiencing. As most targeted therapies are given in conjunction with more traditional chemotherapeutic agents, toxicities of these combination therapies are also evolving. Whilst we increasingly understand the mechanisms underlying the toxicities of chemotherapy and radiotherapy, the addition of targeted treatments requires a new understanding of both toxicity and interacting mechanisms. AIMS: The aims of this review (which formed the basis of an invited plenary lecture at the 2006 Annual conference of the Multinational Association of Supportive Care in Cancer) were to define targeted anti-cancer therapy, to describe its known impact on the mucosa, either alone, or in combination with chemotherapy with or without radiotherapy, and finally to provide an outline for future directions in research into mucosal injury from targeted anti-cancer therapies. METHODOLOGY: Two separate literature reviews were conducted. The combined reviews produced 700 papers of which approximately 70 were included in the review. RESULTS: As with mucosal injury (or mucositis) in general, the studies are hampered by a lack of mucosal injury as primary endpoint, and the variable definitions and levels of reporting. The depth to which mucosal injury was studied was also inadequate. However, it is clear that the key to understanding toxicity is to understand the mechanism of action of the drug, from which it should be possible to predict the toxicities that will occur. CONCLUSIONS: With the increasing use of targeted anti-cancer therapies, mucosal injury, particularly in its manifestations of diarrhoea, and mouth ulcers, is becoming even more prominent. More publications of basic and clinical research in this area is required.
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3.12Impact points
Nuclear factor-kappaB (NF-kappaB) and cyclooxygenase-2 (COX-2) expression in the oral mucosa following cancer chemotherapy.
Oral oncology. 05/2007; 43(4):395-401.
Oral mucositis is a serious and debilitating side effect of cancer treatment. Greater understanding of the pathobiology of mucositis has recently led to the advent of targeted treatments for specific patient populations; however the treatment for mucositis remains palliative for most patients. Nucle... [more] Oral mucositis is a serious and debilitating side effect of cancer treatment. Greater understanding of the pathobiology of mucositis has recently led to the advent of targeted treatments for specific patient populations; however the treatment for mucositis remains palliative for most patients. Nuclear factor-kappaB (NF-kappaB) and cyclooxygenase 2 (COX-2) are thought to play important roles in the development of mucositis. In this study, 20 patients undergoing cytotoxic chemotherapy had oral mucosal biopsies taken prior to and following administration of cytotoxic chemotherapy. The samples were stained for NF-kappaB and COX-2 using routine immunohistochemistry. The results from this preliminary study demonstrated statistically significant increased oral mucosal staining for NF-kappaB and COX-2 following cytotoxic chemotherapy and provide further support for the role of NF-kappaB and COX-2 in the pathogenesis of mucositis.
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2.71Impact points
Velafermin improves gastrointestinal mucositis following irinotecan treatment in tumor-bearing DA rats.
Cancer biology & therapy. 05/2007; 6(4):541-7.
Mucositis is a common, costly and unpleasant side effect of cancer chemotherapy and radiotherapy. Velafermin (FGF-20) has shown the potential to reduce these side effects. Irinotecan is a chemotherapeutic agent which is commonly used in solid tumors, and causes GI mucositis manifested by severe diar... [more] Mucositis is a common, costly and unpleasant side effect of cancer chemotherapy and radiotherapy. Velafermin (FGF-20) has shown the potential to reduce these side effects. Irinotecan is a chemotherapeutic agent which is commonly used in solid tumors, and causes GI mucositis manifested by severe diarrhea. Therefore the primary aim of this study was to investigate whether velafermin reduces the GI mucositis induced by irinotecan. The secondary aim was to test varying schedules of administration of velafermin. Groups of tumor-bearing DA rats (6 per group) were treated with varying doses (4, 8 or 16 mg/kg) of velafermin intraperitoneally either prior to, prior to and during, or after chemotherapy treatment. Rats received a single dose of 200 mg/kg irinotecan intraperitoneally. Rats were monitored closely for the incidence and severity of diarrhea and mortality before being killed 192 h following treatment. Mortality, diarrhea and histopathology were assessed throughout the gastrointestinal tract. Severe or moderate diarrhea occurred in approximately 40% of rats treated with irinotecan alone. This was associated with a 50% mortality rate 96 h following chemotherapy. Velafermin administered at 16 mg/kg prior to irinotecan improved gastrointestinal mucositis as measured by reduced diarrhea and mortality following irinotecan chemotherapy in the DA rat. Rats that received velafermin prior to, or prior to and during irinotecan treatment did develop severe or moderate diarrhea, however it occurred later, in fewer rats and was not associated with mortality. Other dosing regimens were not as effective. This has important implications for the use of velafermin in GI mucositis in humans, and should be further studied.
Following (11)
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Andriana Tran
University of Adelaide -
Mark R Hutchinson
University of Adelaide -
Dorothy Keefe
University of Adelaide -
Joanne Bowen
University of Adelaide -
Ian Hewson
University of Melbourne
