Dorothy Keefe
Research interests
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InterestsCancer Chemotherapy, Cancer Animal Models, Mucositis, Mucosal injury
Publications
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8.08Impact points
Tumor control versus adverse events with targeted anticancer therapies.
Nature reviews. Clinical oncology. 12/2011; 9(2):98-109.
The advent of targeted anticancer therapies over the past few decades has reinvigorated the field of cancer therapeutics, with the promise of increased cancer cure rates accompanied by decreased toxicity. But, has that promise been fulfilled? The short answer is definitely 'no', both because... [more] The advent of targeted anticancer therapies over the past few decades has reinvigorated the field of cancer therapeutics, with the promise of increased cancer cure rates accompanied by decreased toxicity. But, has that promise been fulfilled? The short answer is definitely 'no', both because of disappointing tumor responses and unexpectedly high toxicity, as well as the extremely high financial cost of these agents. However, failing to completely fulfill initial promise does not mean that targeted therapies should be abandoned. Increased progression-free survival might ultimately lead to increased overall survival, and targeted therapies have changed the course of cancers such as breast, lung and renal. Therefore, we would argue that despite some disappointments, targeted therapies have a vital role in future cancer treatment. This Review will discuss the positives and negatives of targeted agents, and propose a way to optimize their use and development to ensure proper personalized cancer medicine that tailors not only the anticancer treatment, but also the antitoxicity strategies, to achieve the best outcome for the patient in terms of both quality and quantity of life.
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3.14Impact points
Patient-reported outcomes in supportive care.
Seminars in oncology. 06/2011; 38(3):358-61.
Traditionally, anticancer therapy has focused on eradication of neoplastic tissue, predominantly by invasive and/or toxic treatments. In modern studies, patient-reported outcomes (PROs) have become more common, and give a true picture of toxicity. Increased consideration of subjective patient perspe... [more] Traditionally, anticancer therapy has focused on eradication of neoplastic tissue, predominantly by invasive and/or toxic treatments. In modern studies, patient-reported outcomes (PROs) have become more common, and give a true picture of toxicity. Increased consideration of subjective patient perspectives of anticancer treatments has allowed a notable shift within supportive oncology. Disparity exists between physician and patient perspectives of symptom severity, despite several common scoring methods. PROs are vital tools in the overall assessment of chronic illnesses, including cancer and associated treatments. Synergistic assessments of objective and subjective observations of symptoms and function are most accurate. PROs include information collected either in a clinic or by a diary system. Patient self-reporting, like any other assessment of health status, is not an absolute measure. Electronic data collection is an increasingly useful way to monitor PROs. Factors that influence quality of life (QOL) are predominantly subjective experiences, and can occur concurrently with pre-existing symptoms, which increases symptom burden. There are several validated systems for assessing PROs; some are concerned with specific conditions like mucositis (Oral Mucositis Weekly Questionnaire [OMDQ]), whereas others cover chronic illness in general (Patient-Reported Outcome Measurement Information System [PROMIS]). The PROMIS framework was developed by the National Health Institute (NHI) to standardize self-reported health measurements within chronic illnesses, including pain, fatigue and emotional distress. The general Assessment of Cancer Therapy (FACT-G) scale was developed to assess many different types of cancer; we will discuss use in oral mucositis as a model. There is more to measuring toxicity than the clinician's objective view of the patient experience. There is still much to be done to validate all the necessary PRO tools so that we can competently measure both toxicity and toxicity-reduction strategies. Current systems to assess PROs continue to have a very positive impact on supportive oncology.
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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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6.70Impact points
Noncardiac vascular toxicities of vascular endothelial growth factor inhibitors in advanced cancer: a review.
The oncologist. 03/2011; 16(4):432-44.
The introduction of molecularly targeted anticancer therapies has brought the promise of longer survival times for select patients with cancers previously considered untreatable. However, it has also brought new toxicities that require understanding and management, sometimes for long periods of time... [more] The introduction of molecularly targeted anticancer therapies has brought the promise of longer survival times for select patients with cancers previously considered untreatable. However, it has also brought new toxicities that require understanding and management, sometimes for long periods of time. Vascular endothelial growth factor inhibitors are associated with a broad range of adverse effects, with vascular toxicity being particularly serious. This review focuses on the current understanding of the pathophysiology and mechanisms of macrovascular toxicities (hypertension, hemorrhage, and thromboembolism), their incidence and severity, the current clinical management, and implications in the advanced cancer setting. Movement of these agents into the early disease setting will alter the impact of these toxicities. Search Strategy and Selection Criteria. Information for this review was collected by searching PubMed/Medline and American Society of Clinical Oncology abstract databases. The medical subject heading terms used included toxicity, hypertension, thromboembolism, hemorrhage, intestinal perforation, risk factors, pharmacokinetics, and metabolism, combined with free text search terms including, but not limited to, VEGF inhibitor*, bevacizumab, sunitinib, and sorafenib. Articles published in English before March 2010 were included, in addition to information from case reports and pharmaceutical agent package inserts.
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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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Pro-inflammatory cytokines play a key role in the development of radiotherapy-induced gastrointestinal mucositis
Radiation Oncology. 01/2010;
Abstract Background 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... [more] Abstract Background 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. Methods 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-1β, IL-6 and TNF in the jejunum and colon. Protein expression of IL-1β, IL-6 and TNF in the intestinal epithelium was investigated using qualitative immunohistochemistry. Results Radiotherapy-induced sub-acute damage was associated with significantly upregulated IL-1β, 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. Conclusions Pro-inflammatory cytokines play a key role in radiotherapy-induced gastrointestinal mucositis in the sub-acute onset setting.
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The potential successes and challenges of targeted anticancer therapies.
Current opinion in supportive and palliative care. 12/2009;
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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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3.93Impact points
HER2 targeted therapies for cancer and the gastrointestinal tract.
Current drug targets. 07/2009; 10(6):537-42.
HER2 (v-erb-b2 erythroblastic leukemia viral oncogene) is a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. Since the discovery of a role for HER2 and other EGF receptors in the development and progression of cancer, they have become targets for a number of ... [more] HER2 (v-erb-b2 erythroblastic leukemia viral oncogene) is a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. Since the discovery of a role for HER2 and other EGF receptors in the development and progression of cancer, they have become targets for a number of targeted anti-cancer drugs. These drugs have proven to be effective in treating and managing a range of cancers, however, recent observations in the clinic have suggested that their administration causes many toxicities, including gastrointestinal toxicity. Drugs with HER2 inhibitory activity fall into two categories; the monoclonal antibodies and small molecule tyrosine kinase inhibitors. Both of these drug classes have been shown to induce symptoms consistent with mucositis development; including nausea and vomiting, diarrhoea and abdominal pain. However, to date, limited studies have been carried out to justify the source of these toxicities. This review summarizes our current knowledge of the toxicities associated with commonly used HER2 targeted therapy drugs, the role of HER2 in cancer and the healthy gastrointestinal tract and the possible mechanisms by which drugs with HER2 inhibitory activity can induce gastrointestinal damage and possibly mucositis in patients.
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2.09Impact points
Role of the cyclooxygenase pathway in chemotherapy-induced oral mucositis: a pilot study.
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 05/2009;
GOALS: Oral mucositis can be a significant and dose-limiting complication of high-dose cancer therapy. Mucositis is a particularly severe problem in patients receiving myeloablative chemotherapy prior to bone marrow or hematopoetic stem cell transplant (HSCT). The cyclooxygenase (COX) pathway mediat... [more] GOALS: Oral mucositis can be a significant and dose-limiting complication of high-dose cancer therapy. Mucositis is a particularly severe problem in patients receiving myeloablative chemotherapy prior to bone marrow or hematopoetic stem cell transplant (HSCT). The cyclooxygenase (COX) pathway mediates tissue injury and pain through upregulation of pro-inflammatory prostaglandins, including prostaglandin E2 (PGE2) and prostacyclin (PGI2). The objective of this small (n = 3) pilot study was to examine the role of the COX pathway in causing mucosal injury and pain in chemotherapy-induced oral mucositis. MATERIALS AND METHODS: We collected blood, saliva, and oral mucosal biopsy specimens from three autologous HSCT patients at the following time-points before and after administration of conditioning chemotherapy: Day -10, +10, +28, and +100, where day 0 is day of transplant. RNA extracted from full-thickness tissue samples was measured by RT-PCR for the following: COX-1, COX-2, microsomal prostaglandin E synthase (mPGES), IL-1beta, and TNF-alpha. Blood and saliva samples were measured by ELISA for PGE2 and PGI2, which are markers of COX activity. Severity of oral mucositis was determined using the Oral Mucositis Index. Severity of pain due to oral mucositis was measured using a Visual Analog Scale. Relationships between the different variables were examined using Spearman rank correlation coefficients. MAIN RESULTS: Mean mucositis and pain scores increased significantly after administration of chemotherapy and then gradually declined. The correlation between changes in mucositis and pain scores was strong and statistically significant. The following additional correlations were statistically significant: between tissue COX-1 and pain; between tissue mPGES and pain; between salivary PGE1 and pain; between salivary PGI2 and pain. Other relationships were not statistically significant. CONCLUSIONS: Our finding of significant associations of pain scores with tissue COX-1 and mPGES, as well as salivary prostaglandins, is suggestive of a role for the cyclooxygenase pathway in mucositis, possibly via upregulation of pro-inflammatory prostaglandins. However, our small sample size may have contributed to the lack of significant associations between COX-2 and other inflammatory mediators with mucosal injury and pain. Thus, additional studies with larger numbers of subjects are warranted to confirm the involvement of the cyclooxygenase pathway in chemotherapy-induced mucositis.
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Links between regimen-related toxicities in patients being treated for colorectal cancer.
Current opinion in supportive and palliative care. 04/2009; 3(1):50-4.
PURPOSE OF REVIEW: To summarize the available evidence on cooccurring gastrointestinal toxicities and their potential link with other symptoms in cancer patients. The information obtained from colorectal cancer patient cohorts will be used as an example. RECENT FINDINGS: In recent years, it has beco... [more] PURPOSE OF REVIEW: To summarize the available evidence on cooccurring gastrointestinal toxicities and their potential link with other symptoms in cancer patients. The information obtained from colorectal cancer patient cohorts will be used as an example. RECENT FINDINGS: In recent years, it has become clear that gastrointestinal toxicities do not occur in isolation in cancer patients. Rather, they may link or associate with many other disturbances. Data have emerged that suggest that many of the complications of cancer chemotherapy occur in clusters and seem to support the sharing of common pathogenesis for clustering toxicities. SUMMARY: During the last few years, research in symptom clusters and cooccurring linked toxicities has markedly changed, progressively shifting from a simplistic descriptive picture to more comprehensive and pathogenetically driven analyses. Still, many questions remain to be answered, and whether and how toxicity aggregations vary during the treatment course remains to be elucidated.
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2.65Impact points
Matrix metalloproteinases: key regulators in the pathogenesis of chemotherapy-induced mucositis?
Cancer chemotherapy and pharmacology. 04/2009;
Chemotherapy is an effective anticancer treatment; however, it induces mucositis in a wide range of patients. Mucositis is the term used to describe the damage caused by radiation and chemotherapy to mucous membranes of the alimentary tract. This damage causes pain and ulceration, vomiting, bloating... [more] Chemotherapy is an effective anticancer treatment; however, it induces mucositis in a wide range of patients. Mucositis is the term used to describe the damage caused by radiation and chemotherapy to mucous membranes of the alimentary tract. This damage causes pain and ulceration, vomiting, bloating and diarrhoea, depending on the area of the alimentary tract affected. Although treatment is available for a small subset of patients suffering from mucositis, the majority rely on pain relief as their only treatment option. Much progress has been made in recent years into understanding the pathobiology underlying the development of mucositis. It is well established that chemotherapy causes prominent small intestinal and colonic damage as a result of up-regulation of stress response genes and pro-inflammatory cytokines. However, better understanding of the mediators of this damage is still required in order to target appropriate treatment strategies. Possible mediators of mucositis which have not been well researched are the matrix metalloproteinases (MMPs). MMPs have been shown to function in several of the pathways which are known to be up-regulated in mucositis and contribute to tissue injury and inflammation in many pathological conditions. This prompts the consideration of MMPs as possibly being key mediators in mucositis development.
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3.99Impact points
Chemotherapy-Induced Modifications to Gastrointestinal Microflora: Evidence and Implications of Change.
Current drug metabolism. 02/2009; 10(1):79-83.
Mucositis is a common side effect of chemotherapy which remains poorly understood. Despite advances in the understanding of oral and small intestinal mucositis over recent years, large intestinal mucositis, including diarrhoea, has not been well defined and the underlying mechanisms of the condition... [more] Mucositis is a common side effect of chemotherapy which remains poorly understood. Despite advances in the understanding of oral and small intestinal mucositis over recent years, large intestinal mucositis, including diarrhoea, has not been well defined and the underlying mechanisms of the condition are yet to be established. The majority of the literature available concerning large intestinal mucositis is based on clinical observations, with very little basic research existing. However, from the little research conducted, it is likely that the intestinal microflora play a role in the development of chemotherapy-induced mucositis. This review will explore the potentially important relationship between intestinal microflora and the subsequent development of chemotherapy-induced mucositis.
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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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2.71Impact points
Faecal microflora and beta-glucuronidase expression are altered in an irinotecan-induced diarrhoea model in rats.
Cancer biology & therapy. 01/2009; 7(12).
Objectives: Chemotherapy-induced diarrhoea (CID) is a well recognised side effect of cancer treatment. However, the pathophysiology behind this debilitating side effect remains unclear. Irinotecan causes cholinergic and delayed onset diarrhoea in patients, in which beta-glucuronidase produced by gut... [more] Objectives: Chemotherapy-induced diarrhoea (CID) is a well recognised side effect of cancer treatment. However, the pathophysiology behind this debilitating side effect remains unclear. Irinotecan causes cholinergic and delayed onset diarrhoea in patients, in which beta-glucuronidase produced by gut bacteria is thought to be involved. Results: Diarrhoea occurred, as expected, following irinotecan treatment. beta-glucuronidase expression increased in the jejunum and colon. Faecal flora changed quantitatively after treatment also, with increases in E. coli, Staphylococcus spp., and Clostridium spp. (all beta-glucuronidase producing), and decreases in Lactobacillus spp., Bifidobacterium spp. (both beneficial bacteria), and Bacteroides spp. (beta-glucuronidase producing, major component of intestinal flora). Methods: Rats were treated with 200 mg/kg irinotecan and killed at various time points up to 72 h. Rats were monitored for diarrhoea. Sections were stained for beta-glucuronidase expression, and faecal DNA was analysed using real time PCR. Conclusions: Irinotecan-induced diarrhoea may be caused by an increase in beta-glucuronidase producing bacteria. However, the increase in bacteria may also be caused by irinotecan, further exaggerating the toxicity of the drug, and emphasising the need for these specific bacteria to be therapeutically targeted for successful treatment regimens to be accomplished.
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5.42Impact points
Patient-reported measurements of oral mucositis in head and neck cancer patients treated with radiotherapy with or without chemotherapy: demonstration of increased frequency, severity, resistance to palliation, and impact on quality of life.
Cancer. 12/2008; 113(10):2704-13.
BACKGROUND: The risk, severity, and patient-reported outcomes of radiation-induced mucositis among head and neck cancer patients were prospectively estimated. METHODS: A validated, patient-reported questionnaire (OMDQ), the FACT quality of life (QOL), and the Functional Assessment of Chronic Illness... [more] BACKGROUND: The risk, severity, and patient-reported outcomes of radiation-induced mucositis among head and neck cancer patients were prospectively estimated. METHODS: A validated, patient-reported questionnaire (OMDQ), the FACT quality of life (QOL), and the Functional Assessment of Chronic Illness Therapy (FACIT) fatigue scales were used to measure mucositis (reported as mouth and throat soreness), daily functioning, and use of analgesics. Patients were studied before radiotherapy (RT), daily during RT, and for 4 weeks after RT. RESULTS: Contrary to previous reports, the risk of mucositis was virtually identical in the 126 patients with oral cavity or oropharynx tumors (99% overall; 85% grade 3-4) compared with 65 patients with tumors of the larynx or hypopharynx (98% overall; 77% grade 3-4). The mean QOL score decreased significantly during RT, from 85.1 at baseline to 69.0 at Week 6, corresponding with the peak of mucositis severity. The mean functional status score decreased by 33% from 18.3 at baseline to 12.3 at Week 6. The impact of mucositis on QOL was proportional to its severity, although even a score of 1 or 2 (mild or moderate) was associated with a significant reduction in QOL (from 93.6 at baseline to 74.7 at Week 6). Despite increases in analgesic use from 34% at baseline to 80% at Week 6, mean mucositis scores exceeded 2.5 at Week 6. CONCLUSIONS: Mucositis occurs among virtually all patients who are undergoing radiation treatment of head and neck cancers. The detrimental effects on QOL and functional status are significant, and opioid analgesia provides inadequate relief. Preventive rather than symptom palliation measures are needed.
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2.65Impact points
Irinotecan-induced mucositis is associated with changes in intestinal mucins.
Cancer chemotherapy and pharmacology. 12/2008;
PURPOSE: Mucositis is a major oncological problem, caused by the cytotoxic effects of cancer chemotherapy and radiotherapy. Irinotecan is used to treat a variety of solid tumours, through the inhibition of DNA topoisomerase I and is linked with severe mucositis and diarrhoea. Mucus production appear... [more] PURPOSE: Mucositis is a major oncological problem, caused by the cytotoxic effects of cancer chemotherapy and radiotherapy. Irinotecan is used to treat a variety of solid tumours, through the inhibition of DNA topoisomerase I and is linked with severe mucositis and diarrhoea. Mucus production appears to be increased, which may contribute to the development of diarrhoea. METHODS: Dark agouti rats were treated with irinotecan, and tissues collected at several time points up to 72 h. Goblet cells and mucin secretion were investigated, as well as mucin expression (Muc2 and Muc4) and kruppel-like factor (Klf) 4 using immunohistochemistry in the gastrointestinal tract. Both goblet cells and cells positive for Muc expression were counted, and analysed statistically using the Mann-Whitney U test with Bonferroni correction. RESULTS: Goblet cells decreased significantly after irinotecan treatment. However, mucin secretion increased. Mucin expression changed significantly after treatment. Muc2 and Muc4 decreased significantly in the villi of the jejunum after treatment, Muc2 and Muc4 decreased significantly in the crypts. Muc2 decreased significantly in the colon. CONCLUSIONS: Irinotecan causes an increase in mucin secretion and a net decrease in mucin-producing goblet cells, and the expression of Muc2 and Muc4 in the gastrointestinal tract is altered following treatment. Increased mucin secretion is likely to be related to altered mucin expression, and may contribute to chemotherapy-induced diarrhoea.
Following (8)
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Emma Bateman
University of Adelaide -
Anna Tsykin
IMVS Pathology -
Stephen T Sonis
Brigham and Women's Hospital -
Cesar A Migliorati
The University of Tennessee Health Science Center -
Rachel J Gibson
University of Adelaide
Topics (2)
