Evaluation and validation of chemotherapy‐specific diarrhoea and histopathology in rats (original) (raw)
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Preliminary Study for Development of an Experimental Model of Cancer Chemotherapy Induced Diarrhea
International Journal of Contemporary Medical Research [IJCMR], 2020
Introduction: Cancer chemotherapy induced diarrhea (CCID) is a frequent problem during anticancer treatment. Patho-physiology of CCID differs between chemotherapeutic agents. Neither there is specific treatment for CCID nor adequate experimental models. The objective of this study was to develop a relevant experimental animal model of CCID, which can help in development of specific therapy for CCID. Material and methods: In this study thirty six albino rats of either sex were divided into 6 groups of 6 animals each. Group I rats received distilled water and served as control. Group II,III,IV, V, VI received 5-Fluorouracil(5-FU) once intra peritoneal(IP) at doses 10,20,30,40 and 50 mg/kg respectively and served as test groups for experimental model of CID. Standard parameters like stool samples for quality& quantity, incidence of diarrhea, histopathology of intestine and fatal outcome in rats were recorded. Results: Out of test groups, rats treated with 5-FU 30mg/ kg IP single dose developed diarrhea in 50% rats,mean time for onset of diarrhea was 84±16.7 hours and duration was 62±9.16 hours, diarrhea subsided within 7 days with mild changes of intestinal histopathology and 16.7% mortality. Occurrence of diarrhea, change in intestinal histopathology was not remarkable with dosage less than 30mg/kg. In 5 FU 40 mg/kg & 50mg/kg group incidence of diarrhea increased to 66.6% but death rate were further increased to 33.3% in5 FU 40 mg/kg& 83.3% with 50mg/kg. Conclusion: The results suggest 5-FU 30mg/kg single dose IP to albino rats can be used as a suitable experimental model for CCID for evaluation of novel potential candidate drugs for treatment of CCID.
Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management
Therapeutic advances in medical oncology, 2010
Diarrhea is one of the main drawbacks for cancer patients. Possible etiologies could be radiotherapy, chemotherapeutic agents, decreased physical performance, graft versus host disease and infections. Chemotherapy-induced diarrhea (CID) is a common problem, especially in patients with advanced cancer. The incidence of CID has been reported to be as high as 50-80% of treated patients (≥30% CTC grade 3-5), especially with 5-fluorouracil bolus or some combination therapies of irinotecan and fluoropyrimidines (IFL, XELIRI). Regardless of the molecular targeted approach of tyrosine kinase inhibitors and antibodies, diarrhea is a common side effect in up to 60% of patients with up to 10% having severe diarrhea. Furthermore, the underlying pathophysiology is still under investigation. Despite the number of clinical trials evaluating therapeutic or prophylactic measures in CID, there are just three drugs recommended in current guidelines: loperamide, deodorized tincture of opium and octreot...
Chemotherapy-induced diarrhea is associated with changes in the luminal environment in the DA rat
Experimental biology and medicine (Maywood, N.J.), 2007
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 onse...
Anti-Colorectal Cancer Chemotherapy-Induced Diarrhoea: Current Treatments and Side-Effects
International Journal of Clinical Medicine, 2014
moreover, about 5% of early deaths associated with combination anti-cancer chemotherapy are due to CID. Chronic post-treatment diarrhoea amongst cancer survivors can persist for more than 10 years greatly effecting long-term quality of life. Gastrointestinal toxicities such as diarrhoea and vomiting are amongst the primary contributors to dose reductions and delays throughout anti-cancer treatment, presenting a significant hurdle in clinical management of anti-cancer regimes and often result in sub-optimum treatment. However, little is known about pathophysiological mechanisms underlying CID. This work provides a review of chemotherapy-induced diarrhoea, current management guidelines, and shortcomings of current treatments as well as emerging and already existing anti-diarrhoeal treatments potentially suitable for CID. R. M. McQuade et al. 394 With global incidence and mortality rates of approximately 1.2 million and 610,000 respectively per year [3], and consequently low 5 and 10 year survival rates, CRC is projected to account for more than 1.6 million deaths annually by 2020 [4], placing it amongst the highest contributors to cancer related deaths globally [5]- .
Supportive Care in Cancer, 2006
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.
Journal of Gastroenterology and Hepatology, 2003
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 timecourse 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 timepoints. 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.
Management of Cancer Treatment–Related Diarrhea
Journal of Pain and Symptom Management, 2000
The cancer treatment-related diarrhea caused by acute graft-versus-host disease (GVHD) and chemotherapeutic agents, particularly fluoropyrimidines and irinotecan, significantly affects patient morbidity and mortality. The mechanisms causing cancer treatment-related diarrhea are not fully understood, but histopathologic evidence points to a multifactorial process that causes an absorptive and secretory imbalance in the small bowel. Cancer treatment-related diarrhea could be life-threatening, yet assessment and treatment are not currently standardized. Several clinicians participated in a closed roundtable meeting to review the mechanisms of chemotherapy-induced diarrhea (CID) and GVHD-induced diarrhea, management issues in cancer treatment-induced diarrhea, and pharmacologic approaches to treatment. The meeting produced a proposal for new treatment guidelines and an algorithm, which include the use of octreotide for the management of CID-and GVHD-induced diarrhea. The development of diarrhea assessment guidelines that expand on the current National Cancer Institute criteria and allow for better patient management was also proposed.
New approaches to prevent intestinal toxicity of irinotecan-based regimens
Cancer treatment …, 2004
Background. Irinotecan is a selective inhibitor of topoisomerase I, an enzyme part of the replication and transcription system of DNA. Irinotecan is employed, with different modalities, in the treatment of metastatic colorectal cancer, and recently it has been officially approved in association with fluorouracil (FU) and leucovorin (LV) as a first-line option in metastatic colorectal cancer. Results. One of the problems linked to the administration of this drug is the high intestinal toxicity, which constitutes its dose limiting toxicity (DLT). In routine practice, loperamide is employed as symptomatic drug for the treatment of CPT-11induced diarrhoea, but is not completely adequate to control the problem. The role of the intestinal bacterial microflora in the pathogenesis of CPT-11-induced intestinal toxicity has been recently discovered. The active metabolite of CPT-11, SN38, is generated from CPT-11 by sieric carboxylesterase, and subsequently conjugated to SN38-G by hepatic UDP-glucuronyltransferase. SN38-G is the inactive metabolite of CPT-11 and is excreted into the small intestine, from which it is eliminated in the faeces. Some studies have shown the ability of intestinal bacterial b-glucoronidases to transform SN38-G into SN38, causing direct damage to the intestinal mucosa. Thus, alternative strategies such as intestinal alkalinization and anti-cyclooxygenase 2 (COX-2) therapy have been explored. Conclusions. In this review, we will illustrate the mechanisms which cause the CPT-11-induced diarrhoea and the potential measures available to prevent it.
Chemotherapy-induced diarrhoea
Current Opinion in Supportive and Palliative Care, 2009
CID is a well recognized side effect of cancer chemotherapy [4-7,12,13] and can be accompanied with blood, mucus, and pain . Between 20 and 40% of all patients