epidermal-growth-factor and Diarrhea

Several GI peptides linked to intestinal barrier function could be involved in the modification of intestinal permeability and the onset of diarrhea during adjuvant chemotherapy. The aim of the study was to evaluate the circulating levels of zonulin, glucagon-like peptide-2 (GLP-2), epidermal growth factor (EGF) and ghrelin and their relationship with intestinal permeability and chemotherapy induced diarrhea (CTD).. Sixty breast cancer patients undergoing an FEC60 regimen were enrolled, 37 patients completed the study. CTD(+) patients were discriminated by appropriate questionnaire and criteria. During chemotherapy, intestinal permeability was assessed by lactulose/mannitol urinary test on day 0 and day 14. Zonulin, GLP-2, EGF and ghrelin circulating levels were evaluated by ELISA tests at five time-points (days 0, 3, 10, 14, and 21).. During FEC60 administration, the lactulose/mannitol ratio was significantly higher on day 14 than at baseline. Zonulin levels were not affected by chemotherapy, whereas GLP-2 and EGF levels decreased significantly. GLP-2 levels on day 14 were significantly lower than those on day 0 and day 3, while EGF values were significantly lower on day 10 than at the baseline. In contrast, the total concentrations of ghrelin increased significantly at day 3 compared to days 0 and 21, respectively. Ten patients (27%) suffered from diarrhea. On day 14 of chemotherapy, a significant increase of the La/Ma ratio occurred in CTD(+) patients compared to CTD(-) patients. With regards to circulating gut peptides, the AUCg of GLP-2 and ghrelin were significantly lower and higher in CTD(+) patients than CTD(-) ones, respectively. Finally in CTD(+) patients a significant and inverse correlation between GLP-2 and La/Ma ratio was found on day 14.. Breast cancer patients undergoing FEC60 showed alterations in the intestinal permeability, which was associated with modifications in the levels of GLP-2, ghrelin and EGF. In CTD(+) patients, a different GI peptide profile and increased intestinal permeability was found in comparison to CTD(-) patients. This evidence deserves further studies for investigating the potentially different intestinal luminal and microbiota conditions.. Clinical trial NCT01382667.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Ductal, Breast; Chemotherapy, Adjuvant; Cholera Toxin; Cyclophosphamide; Diarrhea; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Epirubicin; Female; Fluorouracil; Ghrelin; Glucagon-Like Peptide 2; Haptoglobins; Humans; Intestinal Absorption; Intestinal Mucosa; Italy; Lactulose; Mannitol; Middle Aged; Peptides; Permeability; Prospective Studies; Protein Precursors; Stomatitis; Time Factors; Treatment Outcome

The management of skin toxicity is crucial for efficient afatinib treatment, but the role of tetracycline class antibiotics (TCs) in managing these rashes is relatively unknown.. We reviewed the clinical records of patients who were administered afatinib for the treatment of non-small cell lung cancer harboring epidermal growth factor receptor mutations between October 2014 and November 2016. Twenty-five patients, who received TCs for the management of afatinib-related skin disorders, were enrolled.. Minocycline was administered orally to participants. Afatinib-related toxic effects, such as rash, diarrhea, and paronychia, were observed in 92%, 92%, and 40% of cases, respectively. Although 24% of diarrhea and 4% of paronychia cases were rated grade 3 or higher, no severe cases of rash were observed during afatinib treatment. Of the 18 afatinib dose reductions, 14 (78%), three (17%), and one (6%) resulted from diarrhea, paronychia, and stomatitis, respectively; no patients required a dose reduction because of rash. When minocycline treatment started, 21 patients (84%) had a rash of grade 1 or less, and three patients had a grade 2 rash. A response to afatinib was observed in 18 patients (72%) and the median duration of afatinib administration was 501 days. An adverse event related to minocycline (grade 1 nausea) was observed in one patient.. A large proportion of the study patients started minocycline before grade 2 rash development and the severity of afatinib-related rash was lower than that previously reported. Oral TCs may be beneficial, especially if started early.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Carcinoma, Non-Small-Cell Lung; Diarrhea; Epidermal Growth Factor; Exanthema; Female; Humans; Lung Neoplasms; Male; Middle Aged; Minocycline; Mutation; Paronychia; Pyridines; Severity of Illness Index; Thiazoles

The epidermal growth factor receptor (EGFr) regulates many cellular functions, such as proliferation, apoptosis, and ion transport. Our aim was to investigate whether long term treatment with interferon-γ (IFN-γ) modulates EGF activation of downstream signaling pathways in intestinal epithelial cells and if this contributes to dysregulation of epithelial ion transport in inflammation. Polarized monolayers of T(84) and HT29/cl.19A colonocytes were preincubated with IFN-γ prior to stimulation with EGF. Basolateral potassium transport was studied in Ussing chambers. We also studied inflamed colonic mucosae from C57BL/6 mice treated with dextran sulfate sodium or mdr1a knock-out mice and controls. IFN-γ increased intestinal epithelial EGFr expression without increasing its phosphorylation. Conversely, IFN-γ caused a significant decrease in EGF-stimulated phosphorylation of specific EGFr tyrosine residues and activation of ERK but not Akt-1. In IFNγ-pretreated cells, the inhibitory effect of EGF on carbachol-stimulated K(+) channel activity was lost. In inflamed colonic tissues, EGFr expression was significantly increased, whereas ERK phosphorylation was reduced. Thus, although it up-regulates EGFr expression, IFN-γ causes defective EGFr activation in colonic epithelial cells via reduced phosphorylation of specific EGFr tyrosine residues. This probably accounts for altered downstream signaling consequences. These observations were corroborated in the setting of colitis. IFN-γ also abrogates the ability of EGF to inhibit carbachol-stimulated basolateral K(+) currents. Our data suggest that, in the setting of inflammation, the biological effect of EGF, including the inhibitory effect of EGF on Ca(2+)-dependent ion transport, is altered, perhaps contributing to diarrheal and other symptoms in vivo.

Topics: Animals; Carbachol; Cell Line; Diarrhea; Epidermal Growth Factor; Epithelial Cells; ErbB Receptors; Gene Expression Regulation; Humans; Inflammation; Interferon-gamma; Intestinal Mucosa; Ion Transport; Mice; Mice, Knockout; Miotics; Potassium; Proto-Oncogene Proteins c-akt

The novel cyclin-dependent kinase inhibitor flavopiridol has recently completed Phase I trials for the treatment of refractory neoplasms. The dose-limiting toxicity observed with this agent was severe diarrhea. Because the compound otherwise showed promise, the present study sought to determine possible mechanisms underlying the diarrheal side effects. Flavopiridol was tested for its ability to modify chloride secretory responses of the human colonic epithelial cell line, T84. Studies were conducted in vitro in modified Ussing chambers. High concentrations of flavopiridol (10(-4) M), above those likely to be clinically relevant, had a direct stimulatory effect on chloride secretion, probably ascribable to an increase in cyclic AMP. Lower, clinically relevant concentrations of flavopiridol (10(-6) M) had no effect on chloride secretion by themselves but potentiated responses to the calcium-dependent secretagogue, carbachol. The drug also potentiated responses to thapsigargin and taurodeoxycholate and reversed the inhibitory effects of carbachol and epidermal growth factor on calcium-dependent chloride secretion. Pretreatment with the cyclic AMP-dependent secretagogue, forskolin, potentiated responses to flavopiridol, but not vice versa. Thus, diarrheal side effects induced by flavopiridol are likely multifactorial in origin and may involve interactions with endogenous secretagogues such as acetylcholine and bile acids. A better understanding of the diarrhea induced by flavopiridol should allow optimization of therapy with this otherwise promising drug and/or the development of related agents with improved toxicity profiles.

Topics: Antineoplastic Agents; Carbachol; Chloride Channels; Chlorides; Cholinergic Agonists; Colforsin; Colon; Cyclic AMP; Cyclin-Dependent Kinases; Diarrhea; Epidermal Growth Factor; Flavonoids; Humans; In Vitro Techniques; Intestinal Mucosa; Piperidines

AstraZeneca is developing ZD-1839, an inhibitor of epidermal growth factor receptor 1 (EGFR1) tyrosine kinase, for potential treatment of cancers which overexpress EGF receptors, including non-small cell lung cancer (NSCLC) and pancreatic cancer [196279], [270898]. Phase III studies had started by August 2000 [349551], [350295], [353050], [377656], with first results being expected at the 2001 meetings of the American Association for Cancer Research (AACR) and the American Society for Clinical Oncology (ASCO). The US FDA has issued ZD-1839 with Fast Track status [350295], [353050]. In September 2000, the company expected global NDA filing to take place at the end of 2001, with launch in the next four to five years [383469]. In January 1999, ABN Amro predicted sales of US $25 million in 2004 rising to $82 million in 2005 [316250]. In March 1999, Lehman Brothers predicted a 30% probability that the drug would reach worldwide markets and be launched onto the market in 2004 [336599]. In June 2000, Deutsche Bank predicted sales of US $8 million in 2002, rising to $100 million in 2003 [374500]. In September 2000, analysts Merrill Lynch predicted a launch in 2002 with sales estimated at UK 50 million pounds, rising to 360 million pounds in 2004, while in December 2000, the analysts predicted a filing date in the fourth quarter of 2001 [383742], [396280]. Also in December 2000, Lehman Brothers predicted a filing date late in 2001, and a possible Fast Track review. They also estimated peak sales of US $1 billion [394606].

Topics: Anemia; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase I as Topic; Diarrhea; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Tolerance; Drugs, Investigational; Economics, Pharmaceutical; Epidermal Growth Factor; ErbB Receptors; Gefitinib; Humans; Lung Neoplasms; Nausea; Pancreatic Neoplasms; Quinazolines; Tumor Cells, Cultured

The increased intestinal absorption induced by epidermal growth factor (EGF) is associated with diffuse lengthening of brush border microvilli. The aim of this study was to examine the in vivo effects of oral administration of EGF during infection with enteropathogenic Escherichia coli. New Zealand White rabbits (4 weeks old) received orogastric EGF daily starting 3 days prior to infection with enteropathogenic E. coli RDEC-1 and were compared with sham-treated infected animals and uninfected controls. Weight gain, food intake, fecal E. coli, and stool consistency were assessed daily. On day 10, segments of jejunum, ileum, proximal, and distal colon were assessed for gram-negative bacterial colonization, disaccharidase activities, and epithelial ultrastructure. Effects of EGF on E. coli RDEC-1 proliferation were studied in vitro. E. coli RDEC-1 caused diarrhea and reduced weight gain. Seven days postinfection, the small and large intestines were colonized with numerous bacteria, brush border microvilli were disrupted, and maltase and sucrase activities were significantly reduced in the jejunum. Daily treatment with EGF prevented the occurrence of diarrhea and reduction of weight gain. These effects were associated with significant inhibition of E. coli colonization in the small and large intestine, improved jejunal maltase and sucrase activities and reduced microvillous injury. EGF did not affect the proliferation of E. coli in vitro. The findings suggest that EGF protects the gastrointestinal tract against colonization by enteropathogenic E. coli.

Topics: Administration, Oral; Animals; Diarrhea; Epidermal Growth Factor; Escherichia coli; Escherichia coli Infections; Intestinal Diseases; Intestine, Large; Intestine, Small; Microvilli; Rabbits; Weight Gain

The effect of oral epidermal growth factor (EGF) on histological and biochemical changes in epithelium in the small intestine was studied in colostrum-deprived neonatal pigs. Forty-eight pigs were infected at 4 days of age with 2 x 10(7) plaque-forming units of porcine group A rotavirus and orally fed a simulated sow-milk diet supplemented with 0.0, 0.5, or 1.0 mg/L recombinant human EGF. Sixteen noninfected pigs were fed a diet without EGF supplementation. Infected pigs developed severe diarrhea; they also consumed 25% less food and gained 60% less weight than noninfected pigs. Pigs were killed 8 days postinfection to collect samples at seven equidistant points in the small intestine. Rotavirus infection decreased villus height by 37% and reduced specific activity of lactase by 54%, of leucine aminopeptidase by 43%, and of alkaline phosphatase by 54% in the small intestine, compared with noninfected pigs. Only the supraphysiological dose of EGF (1.0 mg/L) consistently increased villus height in the proximal and mid-small intestine and lactase-specific activity in the mid-small intestine of rotavirus-infected pigs. However, this dose was only partially effective in restoring intestinal mucosal dimensions and enzyme activities. Supplemental EGF did not hasten the resolution of diarrhea. These data indicate that high physiological levels of EGF are beneficial in stimulating recovery of epithelium in the small intestine following rotavirus infection.

Topics: Administration, Oral; Animals; Animals, Newborn; Body Weight; Diarrhea; Disease Models, Animal; Epidermal Growth Factor; Food, Fortified; Intestinal Mucosa; Intestine, Small; Rotavirus Infections; Swine

Topics: Atrophy; Diarrhea; Epidermal Growth Factor; Female; Humans; Infant; Injections, Intravenous; Intestinal Mucosa; Microvilli; Peptide Fragments; Recombinant Proteins; Syndrome