Efficacy of CR3294, a new benzamidine derivative, in the prevention of 5-fluorouracil-induced gastrointestinal mucositis and diarrhea in mice
| Autor: | Albino Bonazzi, Lucio C. Rovati, Ornella Letari, Catherine Booth, Francesco Makovec, Gianfranco Caselli, Paolo Garofalo |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Cancer Research Luminescence medicine.medical_treatment Amidines Toxicology Gastroenterology Mice chemistry.chemical_compound Intestinal mucosa Drug Interactions Pharmacology (medical) Intestinal Mucosa Cancer Mice Inbred BALB C Thiourea Diarrhea Oncology Fluorouracil CR3294 Toxicity Cytokines Original Article Female medicine.symptom medicine.drug Mucositis Antimetabolites Antineoplastic medicine.medical_specialty medicine.drug_class Mice Nude Biology Antimetabolite Benzamidine Inhibitory Concentration 50 Internal medicine medicine Chemotherapy Animals Pharmacology Dose-Response Relationship Drug medicine.disease Xenograft Model Antitumor Assays chemistry Immunology Reactive Oxygen Species |
| Zdroj: | Cancer Chemotherapy and Pharmacology |
| ISSN: | 1432-0843 0344-5704 |
| DOI: | 10.1007/s00280-009-1224-1 |
| Popis: | Purpose Gastrointestinal mucositis, commonly associated with diarrhea, is a dose-limiting toxicity of chemotherapy. The new benzamidine derivative CR3294 reduces tissue damage in animal models of intestinal inflammation. Thus, we tested whether CR3294 had the potential to prevent chemotherapy-induced mucositis. Methods In tests on isolated cells, reactive oxygen species (ROS) formation and cytokine release were measured by chemiluminescence and immunoassays, respectively. In studies in vivo, BDF1 mice were given oral CR3294 (2.5–20 mg/kg) for 3 days before receiving 5-fluorouracil. Intestinal crypt survival, cell apoptosis and proliferation, and diarrhea score were assessed. Additionally, nude mice bearing tumor xenografts were treated with CR3294 and/or 5-fluorouracil, and tumor growth was monitored. Results CR3294 significantly inhibited cytokine release from stimulated leukocytes at concentrations similar to the IC50 (2.9 ± 0.2 μM) for ROS production by these cells. Consistent with these molecular findings, CR3294 dose-dependently protected the intestinal mucosa against 5-fluorouracil-induced toxicity in a mouse model of mucositis. The number of surviving crypts per cross-section in mice receiving 20 mg/kg CR3294 was 2.8-fold that in vehicle-treated animals (18.1 ± 1.9 vs. 6.5 ± 0.9, P |
| Databáze: | OpenAIRE |
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