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Dorothy M K Keefe

Publications and source records attributed to Dorothy M K Keefe.

17 recordsLinked to original sources
PubMed2007

Role of p53 in irinotecan-induced intestinal cell death and mucosal damage.

Irinotecan treatment of colorectal cancers results in high-grade intestinal mucositis in a large proportion of patients. The mechanisms behind irinotecan-induced mucosal injury, however, have yet to be fully explained. The aim of this study was to investigate the role of the p53 protein in the onset of intestinal damage following irinotecan treatment in two different settings. IEC-6 and FHs 74 intestinal cell lines were treated with irinotecan with and without a temporary p53 inhibitor, pifithrin-alpha, and examined for changes in proliferation and survival along with expression of p53 and related proteins. Forty tumour-bearing rats also underwent irinotecan treatment with and without pifithrin-alpha, and the effects on intestinal morphology, gene expression, apoptosis and other toxicities were assessed. Irinotecan caused a dose-dependent reduction in cell viability that was not prevented by pifithrin-alpha in either cell line. Rats responded to irinotecan with diarrhoea, weight loss, histopathological changes to the small and large intestine, increased crypt apoptosis, and a mild inflammatory response. Pifithrin-alpha reduced severity and duration of intestinal apoptosis; however, it did not significantly affect other parameters including p53 expression. Temporary inhibition of p53 activation does not markedly prevent intestinal cell death or mucositis following irinotecan treatment. Irinotecan may act through upregulation of proapoptotic proteins Bax and Bak to induce cell death.

Animals↗
PubMed2007

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

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, 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.

Animals↗
PubMed2006

Mucosal injury from targeted anti-cancer therapy.

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.

Antineoplastic Agents↗
PubMed2006

Nuclear factor-kappaB (NF-kappaB) and cyclooxygenase-2 (COX-2) expression in the oral mucosa following cancer chemotherapy.

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.

Aged↗
PubMed2006

Irinotecan changes gene expression in the small intestine of the rat with breast cancer.

PURPOSE: The aetiology of mucositis is complex involving change in gene expression, altered apoptosis and interaction between epithelial and subepithelial compartments. This is the first investigation using microarray to assess chemotherapy-induced changes in the gut. The aims of this study were to identify genes that are altered by irinotecan, to determine how these genes contribute to apoptosis and to identify any potential gene families and pathways that are important for mucositis development. METHODS: Tumour-bearing female dark Agouti rats were administered twice with 150 mg/kg of irinotecan and killed 6 h after the final dose. Jejunal tissue was harvested and RNA was isolated. cDNA was synthesised and purified, prior to hybridisation and microarray analysis. A 5-K oligo clone set was used to investigate gene expression. Results from the microarray were quantified using RT-PCR. RESULTS: Many genes were significantly up- or down-regulated by irinotecan. In particular, multiple genes implicated in the mitogen-activated protein kinase (MAPK) signalling pathway were differentially regulated following treatment. These included interleukin 1 receptor, caspases, protein kinase C and dual-specificity phosphatase 6. RT-PCR was used to confirm effects of irinotecan on caspase-1 expression in jejunal tissue and was significantly increased 6 h after treatment with irinotecan. CONCLUSIONS: This study has identified MAP kinase signalling as being involved with irinotecan-induced intestinal damage and confirms previous findings with radiation-induced oral mucosal damage, which also implicated this pathway. Microarrays are emerging as a valuable tool in mucositis research by linking such findings. The common pathway of chemotherapy- and radiotherapy-induced damage, which utilises the caspase-cascade, may be a useful target to prevent apoptosis following cancer treatment.

Adenocarcinoma↗
PubMed2006

Cancer chemotherapy-induced diarrhoea and constipation: mechanisms of damage and prevention strategies.

BACKGROUND: Diarrhoea and constipation are common toxicities of chemotherapy, and both are poorly understood. They are manifestations of alimentary mucositis, a condition which affects the entire gastrointestinal tract. DISCUSSION: The absolute percentage of patients that have diarrhoea or constipation as a result of their treatment has yet to be fully defined, although general estimates place 10% of patients with advanced cancer as being afflicted. Although there has been some major progress in recent years with understanding the mechanisms of oral and small intestinal mucositis, diarrhoea and constipation have received very little attention. Although diarrhoea is a well-recognised side-effect of both chemotherapy and radiotherapy, very little research has been conducted on the mechanisms behind diarrhoea or its treatment. Much of the information in the published literature is based on clinical observations with very little basic science existing. Constipation is not as well recognised and very little is known about its mechanisms. OBJECTIVES: This review will examine in detail the potentially complex pathogenesis of post-chemotherapy diarrhoea in both animal models and the clinical setting. Furthermore, it will explore what is known about chemotherapy-induced constipation. It will then outline an evidence-based pathway for the investigation and treatment of post-chemotherapy diarrhoea and constipation.

Animals↗
PubMed2006

Intestinal mucositis: the role of the Bcl-2 family, p53 and caspases in chemotherapy-induced damage.

Intestinal mucositis occurs as a consequence of cytotoxic treatment through multiple mechanisms including induction of crypt cell death (apoptosis) and cytostasis. The molecular control of these actions throughout the gastrointestinal tract has yet to be fully elucidated; however, they are known to involve p53, the Bcl-2 family and caspases. This review will provide an overview of current research as well as identify areas where gaps in knowledge exist.

Animals↗
PubMed2005

Palifermin reduces diarrhea and increases survival following irinotecan treatment in tumor-bearing DA rats.

Mucositis is a common side effect of cancer chemotherapy for which there is currently no treatment. Irinotecan is a commonly used effective chemotherapeutic agent, causing severe gastrointestinal mucositis and diarrhea. Previous research suggests that palifermin is potentially antimucotoxic. The primary aim of this study was to determine whether palifermin was effective in ameliorating irinotecan-induced gastrointestinal mucositis. We also determined the protective effects of single large and multiple small doses of palifermin. Tumor-bearing DA rats were treated with a single large (10 mg/kg) dose of palifermin 3 days prior to, or multiple small (3 mg/kg day for 3 days) doses of palifermin or vehicle control prior to, receiving 2 doses of 150 mg/kg irinotecan. Animals were killed at 6, 24, 48, 72, 96, 120, or 144 hr after treatment. The primary endpoints were diarrhea and mortality. Gastrointestinal morphometry, histopathology and apoptosis were assessed. Tumor weights and mitoses were measured to ensure palifermin did not promote tumor growth. Data were analyzed using Peritz' F-test, Student's t-test and Tukey-Kramer multiple comparison test. Animals pretreated with palifermin tolerated irinotecan treatment better than control animals with less severe diarrhea (5% in animals receiving 10 mg/kg palifermin, 11% in animals receiving 3 x 3 mg/kg palifermin and 28% in animals receiving irinotecan only) and reduced mortality (2% in animals receiving 10 mg/kg palifermin, 11% in animals receiving 3 x 3 mg/kg palifermin and 28% in animals receiving irinotecan only). Small and large intestinal weights were maintained. Intestinal morphometry was not maintained in palifermin-pretreated rats despite being increased prior to irinotecan treatment. Palifermin pretreatment did not prevent apoptosis that peaked at 6 hr in the jejunum or colon, but prevented apoptosis at 96 hr in the small intestine. Palifermin pretreatment in both treatment regimens significantly reduces diarrhea and mortality following irinotecan administration without adversely affecting tumor growth. This positive response warrants further investigation, particularly in humans.

Adenocarcinoma↗
PubMed2005

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

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 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.

Adult↗
PubMed2004

Gastrointestinal mucositis.

OBJECTIVE: To review the management of radiotherapy- and chemotherapy-induced gastrointestinal mucositis. DATA SOURCE: Articles and research studies. CONCLUSION: Gastrointestinal damage is becoming a common dose-limiting toxicity. However, there is only limited research into the mechanism and possible treatment of this toxicity. IMPLICATIONS FOR NURSING PRACTICE: It is important to document the frequency and severity of gastrointestinal mucositis, and to alleviate symptoms wherever possible.

Antineoplastic Agents↗
PubMed2004

Novel therapies.

OBJECTIVE: To highlight selected research directed to new drug and device technologies to manage mucositis in cancer patients and to illustrate potential impact of successful therapies. DATA SOURCES: Published research articles and abstracts, clinical experience. CONCLUSION: Advances in molecular modeling of mucosal injury in cancer patients have created new opportunities for therapy. Research is analyzing the impact of single-agent interventions; varying degrees of efficacy are being reported. Once optimal dosing strategies for single-agent management are defined, the opportunity for multi-agent therapies will emerge. IMPLICATIONS FOR NURSING PRACTICE: The oncology nurse plays a pivotal role in assessing and managing mucositis in cancer patients.

Cryotherapy↗
PubMed2003

Gastrointestinal mucositis: a new biological model.

The history of research into gastrointestinal mucositis (GIM), and how the future directions are informed by the progress made in the study of oral mucositis (OM) are discussed. It is proposed that OM and GIM should both be considered to be elements of alimentary mucositis (AM), which covers mucosal damage through the entire alimentary tract, with regional differences being due to the specialized needs of each area.

Animals↗
PubMed2003

Irinotecan causes severe small intestinal damage, as well as colonic damage, in the rat with implanted breast cancer.

BACKGROUND AND AIMS: Irinotecan (CPT-11) is a chemotherapeutic drug for cancer that causes severe diarrhea by an uncertain mechanism. The aim of the present study was to investigate the time-course of apoptosis and whole intestinal damage after irinotecan to further elucidate the mechanism behind the diarrhea. METHODS: Groups of breast cancer-bearing dark agouti (DA) rats were treated with 100, 150 or 200 mg/kg doses of irinotecan or vehicle control daily for two days, and killed at 6, 24, 72 or 96 h after treatment. Apoptosis and morphometry were examined in both the small and large intestines. Histopathology and goblet cell numbers were recorded. Data were analyzed using the Peritz' F-test. RESULTS: Irinotecan increased apoptosis and caused villous atrophy and crypt hypoplasia in the small intestine, and increased apoptosis, crypt hypoplasia, crypt dilation and mucus secretion in the large intestine. Irinotecan at 100 and 150 mg/kg caused crypt hypoplasia at 6 and 24 h, with rebound hyperplasia at 72 and 96 h. At 200 mg/kg, irinotecan caused a more pronounced crypt hypoplasia earlier and all animals died by 96 h. Apoptosis peaked at 6 h and remained elevated over the remainder of the time-points. This was not dose-dependent. Irinotecan at all doses altered colonic, but not jejunal, goblet cells. Irinotecan increased colonic mucus secretion. CONCLUSIONS: We conclude that irinotecan causes diarrhea by inducing apoptosis and hypoproliferation in both the small and large intestines, and causes colonic damage with changes in goblet cells and mucin secretion.

Adenocarcinoma↗
PubMed2002

The effect of keratinocyte growth factor on tumour growth and small intestinal mucositis after chemotherapy in the rat with breast cancer.

PURPOSE: Mucositis from cancer chemotherapy is a common problem for which there is no definitive treatment. It produces significant morbidity and occasional mortality. Prevention and successful treatment could significantly enhance the quality of life of patients, and improve survival; however any potential preventative agent must not enhance tumour growth. The aims of this study were to assess the effect of keratinocyte growth factor (KGF) on breast tumour growth, and in preventing small intestinal mucositis induced by methotrexate (MTX). METHODS: Tumour-bearing rats received KGF or saline for 5 days prior to either MTX or saline treatment, and were killed 24 h after the last MTX injection. The weights of the tumour, small and large intestines, and liver were recorded. Apoptosis was assessed by TUNEL assay in the tumour and jejunum. Intestinal morphometry was used to assess villus area, crypt length and mitotic crypt count. Tumour proliferation was assessed by mitotic count. RESULTS: KGF increased the weight of the small intestine prior to chemotherapy but the weight was not maintained after chemotherapy. KGF synergized with MTX to increase apoptosis in both intestinal crypts and the breast cancer. KGF also reduced tumour size. CONCLUSIONS: We conclude that KGF had a modest effect on intestinal growth prior to chemotherapy. It did not protect the gut from mucositis, nor did it worsen morphometry. It reduced tumour size.

Adenocarcinoma↗
PubMed2002

Effect of interleukin-11 on ameliorating intestinal damage after methotrexate treatment of breast cancer in rats.

Gastrointestinal mucositis after cancer chemotherapy is an increasing problem that is essentially untreatable once established, although it gradually remits. The aim of this study was to investigate the time-course and effect of interleukin-11 (IL-11) on apoptosis and intestinal morphometry as measures of mucositis. Female DA rats were implanted subcutaneously with syngeneic breast cancer and treated with methotrexate (MTX). Intestinal morphometry was used to assess villus area, crypt length, and mitotic count per crypt. Apoptosis was assessed by TUNEL assay in the tumor and jejunum. Tumor proliferation was assessed by mitotic count. The time-course study showed that MTX increased apoptosis by 28-fold in the crypts of the small intestine and by 3-fold in the tumor, and peaked at 6 hr after chemotherapy. IL-11 (100 microg/kg/twice daily subcutaneously) maintained intestinal weight, and reduced the severity of mucositis, as measured by villus area, crypt length, and mitotic count per crypt. IL-11 at higher doses (200 microg and 400 microg/kg/twice daily subcutaneously), did not further improve villus area, crypt length, and mitotic count per crypt. IL-11 did not affect tumor apoptosis or proliferation. We conclude that IL-11 attenuated mucositis by maintaining intestinal weight and morphometry. IL-11 did not prevent apoptosis, but rather induced compensatory crypt cell proliferation.

Adenocarcinoma↗