Ann S J Yeoh

Publications of Ann S J Yeoh

• Pro-inflammatory cytokines play a key role in the development of radiotherapy-induced gastrointestinal mucositis.

  Authors: Zhi Yi Ong, Rachel J Gibson, Joanne M Bowen, Andrea M Stringer, Jocelyn M Darby, Richard M Logan, Ann Sj Yeoh, Dorothy M Keefe

  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 ofMucositis 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.

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

  Authors: Andrea M Stringer, Rachel J Gibson, Joanne M Bowen, Richard M Logan, Kimberly Ashton, Ann S J Yeoh, Noor Al-Dasooqi, Dorothy M K Keefe

  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 ofChemotherapy-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.

• VSL#3 probiotic treatment reduces chemotherapy-induced diarrhea and weight loss.

  Authors: Joanne M Bowen, Andrea M Stringer, Rachel J Gibson, Ann S J Yeoh, Sarah Hannam, Dorothy M K Keefe

  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 theBACKGROUND: 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.

• A novel animal model to investigate fractionated radiotherapy-induced alimentary mucositis: the role of apoptosis, p53, nuclear factor-kappaB, COX-1, and COX-2.

  Authors: Ann S J Yeoh, Rachel J Gibson, Eric E K Yeoh, Joanne M Bowen, Andrea M Stringer, Kar A Giam, Dorothy M K Keefe

  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 inRadiation-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.

• The role of pro-inflammatory cytokines in cancer treatment-induced alimentary tract mucositis: pathobiology, animal models and cytotoxic drugs.

  Authors: Richard M Logan, Andrea M Stringer, Joanne M Bowen, Ann S J Yeoh, Rachel J Gibson, Stephen T Sonis, Dorothy M K Keefe

  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 theAlimentary 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.

• Chemotherapy-induced mucositis: the role of gastrointestinal microflora and mucins in the luminal environment.

  Authors: Andrea M Stringer, Rachel J Gibson, Joanne M Bowen, Richard M Logan, Ann S J Yeoh, Dorothy M K Keefe

  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 effectCollectively, 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.

• Velafermin improves gastrointestinal mucositis following irinotecan treatment in tumor-bearing DA rats.

  Authors: Rachel J Gibson, Andrea M Stringer, Joanne M Bowen, Richard M Logan, Ann S J Yeoh, Jaimi Burns, Enrique Alvarez, Dorothy M K Keefe

  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 aMucositis 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.

• Chemotherapy-induced diarrhea is associated with changes in the luminal environment in the DA rat.

  Authors: Andrea M Stringer, Rachel J Gibson, Richard M Logan, Joanne M Bowen, Ann S J Yeoh, Jaimi Burns, Dorothy M K Keefe

  Experimental biology and medicine (Maywood, N.J.). 02/2007; 232(1):96-106.

  The microflora of the gastrointestinal tract (GIT) are a complex ecosystem, performing a number of beneficial functions. Irinotecan causes both early and late diarrhea, the latter possibly caused, inThe microflora of the gastrointestinal tract (GIT) are a complex ecosystem, performing a number of beneficial functions. Irinotecan causes both early and late diarrhea, the latter possibly caused, in part, by changes in the microflora of the GIT. Female DA rats were given atropine subcutaneously, prior to a single 200 mg/kg intraperitoneal dose of irinotecan. Animals were monitored for diarrhea and killed at 30 and 60 mins, 2, 6, 12, 24, 48, and 72 hrs after chemotherapy administration. Control rats received no treatment. Fecal samples and stomach, jejunum, and colon samples were collected and stored at -70 degrees C until required. Standard microbiological culture techniques were used to grow and isolate the flora. Biochemical tests were used to identify the bacteria. The level of growth was noted for relative comparison between time points and graded accordingly. Early diarrhea was observed in the rats from 2-6 hrs after treatment, after which time the diarrhea resolved. Late onset diarrhea was apparent 72 hrs after treatment. Changes were seen in the flora of the stomach, jejunum, colon and feces. The majority of microflora changes were seen 6, 12, and 24 hrs after treatment, with a relative increase or decrease in the presence of bacteria in comparison with control rats. In some rats bacteria were not observed at all time points, and different bacteria not seen in control animals were identified in rats treated with irinotecan. These changes were observed up to 72 hrs after treatment. In conclusion, irinotecan treatment causes changes in the flora of the stomach, jejunum, colon, and feces of rats and is associated with the development of diarrhea. These changes in flora may have systemic effects and in particular may contribute to the development of chemotherapy-induced mucositis.

• Nuclear factor kappaB (NFkappaB) and cyclooxygenase-2 (Cox-2) expression in the irradiated colorectum is associated with subsequent histopathological changes.

  Authors: Ann S J Yeoh, Joanne M Bowen, Rachel J Gibson, Dorothy M K Keefe

  International journal of radiation oncology, biology, physics. 01/2006; 63(5):1295-303.

  PURPOSE: Recent studies have proposed that mucositis development is the same throughout the gastrointestinal tract (GIT), as it is formed from one structure embryologically. Radiation-induced oralPURPOSE: Recent studies have proposed that mucositis development is the same throughout the gastrointestinal tract (GIT), as it is formed from one structure embryologically. Radiation-induced oral mucositis studies have outlined the key involvement of nuclear factor kappaB (NFkappaB) and cyclooxygenase-2 (Cox-2) in its pathobiology. The purpose of this study was therefore to investigate the expression of NFkappaB and Cox-2 in the irradiated colorectum and to correlate these with the associated histopathologic changes. METHODS AND MATERIALS: Colorectal tissues from 28 colorectal cancer patients treated with preoperative radiotherapy were analyzed for histopathologic changes using a variety of tissue staining methods. The expression of NFkappaB and Cox-2 in these tissues was investigated using immunohistochemistry. Changes in expression of these proteins were then correlated with the histopathologic changes. RESULTS: Radiation therapy caused injury to the normal colorectal tissue surrounding tumor site, particularly around the blood vessels. These changes were reflected in changes in NFkappaB and Cox-2 expression. CONCLUSIONS: We conclude that different regions of the GIT, the colorectum, and oral cavity have similar underlying mechanisms of radiation-induced mucositis. Understanding these mechanisms will allow new approaches to be developed to specifically target steps in the evolution of alimentary mucositis.