Efficacy of CR3294, a new benzamidine derivative, in the prevention of 5-fluorouracil-induced gastrointestinal mucositis and diarrhea in mice.

Abstract

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 IC(50) (2.9 +/- 0.2 muM) 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 < 0.001). Moreover, CR3294 decreased the cumulative diarrhea score by 50%, reduced by nearly 70% the incidence of severe episodes, and increased by 3-fold the number of mice without diarrhea. CR3294 neither affected the growth of tumor xenografts nor protected tumors from the cytotoxic activity of 5-fluorouracil.

CONCLUSIONS:

This study demonstrates that CR3294 acts on key molecular targets to reduce the signs of mucositis and the occurrence of diarrhea in mice exposed to the chemotherapy drug 5-fluorouracil.

• Authors: Ornella Letari, Catherine Booth, Albino Bonazzi, Paolo Garofalo, Francesco Makovec, Lucio C Rovati, Gianfranco Caselli
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 66 Issue 5 Pg. 819-27 (Oct 2010) ISSN: 1432-0843 [Electronic] Germany
• PMID: 20041326 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amidines
• Antimetabolites, Antineoplastic
• CR 3294
• Cytokines
• Reactive Oxygen Species
• Thiourea
• Fluorouracil

Topics

• Amidines (administration & dosage, pharmacology)
• Animals
• Antimetabolites, Antineoplastic (pharmacology, toxicity)
• Cytokines (drug effects, metabolism)
• Diarrhea (chemically induced, prevention & control)
• Dose-Response Relationship, Drug
• Drug Interactions
• Female
• Fluorouracil (pharmacology, toxicity)
• Inhibitory Concentration 50
• Intestinal Mucosa (drug effects, pathology)
• Luminescence
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mucositis (chemically induced, prevention & control)
• Reactive Oxygen Species
• Thiourea (administration & dosage, analogs & derivatives, pharmacology)
• Xenograft Model Antitumor Assays