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

Letari O, Booth C, Bonazzi A, Garofalo P, Makovec F, Rovati LC, Caselli G - Cancer Chemother. Pharmacol. (2009)

Bottom Line: The new benzamidine derivative CR3294 reduces tissue damage in animal models of intestinal inflammation.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.CR3294 neither affected the growth of tumor xenografts nor protected tumors from the cytotoxic activity of 5-fluorouracil.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, Rottapharm, Monza, Italy.

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.

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Effects of increasing concentrations of CR3294 on ROS production by PMNL stimulated with PMA. Between-group differences are all P < 0.05 from 6 min onward (Holm–Sidak method). Similar results were obtained in 3 independent experiments performed in quadruplicate. ROS reactive oxygen species, PMNL polymorphonuclear leukocytes, PMA phorbol-12-myristate-13-acetate, RLU relative luminescence units
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Fig1: Effects of increasing concentrations of CR3294 on ROS production by PMNL stimulated with PMA. Between-group differences are all P < 0.05 from 6 min onward (Holm–Sidak method). Similar results were obtained in 3 independent experiments performed in quadruplicate. ROS reactive oxygen species, PMNL polymorphonuclear leukocytes, PMA phorbol-12-myristate-13-acetate, RLU relative luminescence units

Mentions: Phorbol-12-myristate-13-acetate (PMA) rapidly increased ROS production by PMNL, as measured by chemiluminescence. CR3294 inhibited this response in a concentration dependent manner, with an IC50 value of 2.9 ± 0.2 μM and a maximal inhibition of about 76% at 10 μM. The effects of treatment and time, and their interaction, were all significant (P < 0.01, two-way ANOVA). Post hoc analysis showed significant differences across all groups from 6 min onward (Fig. 1).Fig. 1


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

Letari O, Booth C, Bonazzi A, Garofalo P, Makovec F, Rovati LC, Caselli G - Cancer Chemother. Pharmacol. (2009)

Effects of increasing concentrations of CR3294 on ROS production by PMNL stimulated with PMA. Between-group differences are all P < 0.05 from 6 min onward (Holm–Sidak method). Similar results were obtained in 3 independent experiments performed in quadruplicate. ROS reactive oxygen species, PMNL polymorphonuclear leukocytes, PMA phorbol-12-myristate-13-acetate, RLU relative luminescence units
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2926937&req=5

Fig1: Effects of increasing concentrations of CR3294 on ROS production by PMNL stimulated with PMA. Between-group differences are all P < 0.05 from 6 min onward (Holm–Sidak method). Similar results were obtained in 3 independent experiments performed in quadruplicate. ROS reactive oxygen species, PMNL polymorphonuclear leukocytes, PMA phorbol-12-myristate-13-acetate, RLU relative luminescence units
Mentions: Phorbol-12-myristate-13-acetate (PMA) rapidly increased ROS production by PMNL, as measured by chemiluminescence. CR3294 inhibited this response in a concentration dependent manner, with an IC50 value of 2.9 ± 0.2 μM and a maximal inhibition of about 76% at 10 μM. The effects of treatment and time, and their interaction, were all significant (P < 0.01, two-way ANOVA). Post hoc analysis showed significant differences across all groups from 6 min onward (Fig. 1).Fig. 1

Bottom Line: The new benzamidine derivative CR3294 reduces tissue damage in animal models of intestinal inflammation.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.CR3294 neither affected the growth of tumor xenografts nor protected tumors from the cytotoxic activity of 5-fluorouracil.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, Rottapharm, Monza, Italy.

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.

Show MeSH
Related in: MedlinePlus