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

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.

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

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.

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.

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

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.

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

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-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. RESULTS: 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. CONCLUSIONS: Pro-inflammatory cytokines play a key role in radiotherapy-induced gastrointestinal mucositis in the sub-acute onset setting.