melphalan and Intestinal-Diseases

Conditioning therapy with high-dose melphalan (HDM) is associated with a high risk of gut toxicity, fever and infections in haematopoietic stem cell transplant (HSCT) recipients. However, validated preclinical models that adequately reflect clinical features of melphalan-induced toxicity are not available. We therefore aimed to develop a novel preclinical model of melphalan-induced toxicity that reflected well-defined clinical dynamics, as well as to identify targetable mechanisms that drive intestinal injury.. Male Wistar rats were treated with 4-8 mg/kg melphalan intravenously. The primary endpoint was plasma citrulline. Secondary endpoints included survival, weight loss, diarrhea, food/water intake, histopathology, body temperature, microbiota composition (16S sequencing) and bacterial translocation.. Melphalan 5 mg/kg caused self-limiting intestinal injury, severe neutropenia and fever while impairing the microbial metabolome, prompting expansion of enteric pathogens. Intestinal inflammation was characterized by infiltration of polymorphic nuclear cells in the acute phases of mucosal injury, driving derangement of intestinal architecture. Ileal atrophy prevented bile acid reabsorption, exacerbating colonic injury via microbiota-dependent mechanisms.. We developed a novel translational model of melphalan-induced toxicity, which has excellent homology with the well-known clinical features of HDM transplantation. Application of this model will accelerate fundamental and translational study of melphalan-induced toxicity, with the clinical parallels of this model ensuring a greater likelihood of clinical success.

Topics: Animals; Bacterial Translocation; Bile Acids and Salts; Fever; Gastrointestinal Microbiome; Hematopoietic Stem Cell Transplantation; Inflammation; Intestinal Diseases; Male; Melphalan; Microbiota; Neutropenia; Rats; Rats, Wistar; Transplantation Conditioning; Transplantation, Autologous

Oral and/or intestinal mucositis is a severe complication of hematopoietic SCT. Keratinocyte growth factor (KGF) has proven activity in the prevention of oral mucositis. We examined the efficacy of KGF in the prevention of intestinal mucositis. From January 2006 until December 2007, 35 consecutive patients underwent autologous SCT (auto-SCT) in our institution. A total of 15 consecutive patients who underwent auto-SCT from March 2007 to December 2007 received KGF for the prevention of mucositis and were included in the study group A, whereas 20 consecutive patients treated from January 2006 to March 2007, were included in the historical control group B. Oral and intestinal mucositis were significantly less severe in group A (P=0.002 and P<0.001, respectively). These results were confirmed with the use of video-capsule endoscopy. Patients in group A had a significantly lower incidence of neutropenic fever (P=0.026). Severe intestinal mucositis was significantly associated with a higher incidence of documented infections too (P=0.019). KGF is effective in the prevention of intestinal mucositis in patients undergoing auto-SCT. Patients with severe intestinal mucositis run a higher risk to develop infections.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Capsule Endoscopy; Carmustine; Cytarabine; Female; Fibroblast Growth Factor 7; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Intestinal Diseases; Male; Melphalan; Middle Aged; Mucositis; Podophyllotoxin; Transplantation, Autologous

Topics: Amyloid; Amyloidosis; Calcinosis; Female; Humans; Intestinal Diseases; Intestinal Mucosa; Intestine, Large; Melphalan; Middle Aged; Prednisolone; Protein Denaturation; Treatment Outcome

Topics: Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Humans; Immunoglobulin kappa-Chains; Intestinal Diseases; Male; Melphalan; Middle Aged; Plasmacytoma; Prednisolone; Remission Induction; Stomach Diseases

A small pre-treatment 'priming' dose of cyclophosphamide will reduce gut damage due to high dose i.v. melphalan in mice and sheep but efforts to demonstrate this effect in man have been hampered by difficulty in the measurement of gut damage. We have evaluated the 51CR EDTA absorption test, a new method for measuring intestinal permeability, as a means of assessing damage due to high dose melphalan. The test was reliable, with a narrow normal range, easy to use and well tolerated. It detected an increase in intestinal permeability after high dose melphalan with a maximum occurring between 9 and 15 days after treatment and subsequently returning to normal. It was shown in 19 patients that a pre-treatment dose of cyclophosphamide was capable of significantly reducing the abnormalities in intestinal permeability which resulted from high dose melphalan.

Topics: Adult; Bone Marrow Transplantation; Chromium Radioisotopes; Cyclophosphamide; Dose-Response Relationship, Drug; Edetic Acid; Female; Humans; Intestinal Absorption; Intestinal Diseases; Intestinal Mucosa; Male; Melphalan; Middle Aged; Neoplasms; Time Factors

The effect of epidermal growth factor (hEGF) on intestinal epithelial damage by melphalan was explored in CBA mice. Human EGF was administered in doses of 100 micrograms kg-1 or 1000 micrograms kg-1 using a variety of schedules. Mucosal damage was assessed 4, 8 and 13 days later, by [14C]-xylose uptake and by microcolony survival of jejunum, ileum and colon. The only regimen to show enhanced jejunal crypt survival was administration of hEGF, 100 micrograms kg-1, i.p., 8 hourly, beginning 24 h before melphalan treatment. Oral administration of hEGF had no effect on melphalan induced damage nor on subsequent recovery of intestinal mucosa. Activity of hEGF in mice was confirmed by demonstration of precocious eyelid opening in newborn mice. No consistent protective or restorative effect of hEGF on melphalan-induced intestinal epithelial damage could be demonstrated with the doses and schedules used.

Topics: Animals; Drug Administration Schedule; Epidermal Growth Factor; Female; Intestinal Diseases; Intestinal Mucosa; Male; Melphalan; Mice; Mice, Inbred CBA; Regeneration