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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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Cumulative diarrhea score in mice exposed to 5-FU. Animals (n = 15 per group) were pretreated with CR3294 or its vehicle 72, 48, and 24 h before receiving 2 doses (6 h apart) of the cytotoxic agent. Scores were recorded as 0, 1, 2, or 3 where 0 is normal stools, 1 is loose stools, 2 is moderate diarrhea, and 3 is severe diarrhea
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Fig3: Cumulative diarrhea score in mice exposed to 5-FU. Animals (n = 15 per group) were pretreated with CR3294 or its vehicle 72, 48, and 24 h before receiving 2 doses (6 h apart) of the cytotoxic agent. Scores were recorded as 0, 1, 2, or 3 where 0 is normal stools, 1 is loose stools, 2 is moderate diarrhea, and 3 is severe diarrhea

Mentions: We then assessed in a proof-of-concept study whether CR3294, at the dose (20 mg/kg) that significantly decreased mucosal damage, also reduced the incidence and/or severity of diarrhea in mice exposed to 5-FU. Nearly all mice (13 out of 15) receiving 5-FU and vehicle developed diarrhea starting from day 4. The number of mice without diarrhea for the entire study was 3-fold higher in the group treated with CR3294 than in vehicle-treated animals. Moreover, pretreatment with CR3294 reduced the cumulative symptom score by 50% (Fig. 3). Moderate-to-severe diarrhea (grade 2–3) was more frequent in the vehicle-treated group than in the group treated with CR3294 (13 vs. 4 observations; nearly 70% reduction). Similar results were found when we analyzed the 7-day study period during which all mice were alive (Fig. 4). Statistical analysis showed a significant difference (P < 0.05, Mann–Whitney rank sum test) between the two groups in the median diarrhea score.Fig. 3


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)

Cumulative diarrhea score in mice exposed to 5-FU. Animals (n = 15 per group) were pretreated with CR3294 or its vehicle 72, 48, and 24 h before receiving 2 doses (6 h apart) of the cytotoxic agent. Scores were recorded as 0, 1, 2, or 3 where 0 is normal stools, 1 is loose stools, 2 is moderate diarrhea, and 3 is severe diarrhea
© Copyright Policy
Related In: Results  -  Collection

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

Fig3: Cumulative diarrhea score in mice exposed to 5-FU. Animals (n = 15 per group) were pretreated with CR3294 or its vehicle 72, 48, and 24 h before receiving 2 doses (6 h apart) of the cytotoxic agent. Scores were recorded as 0, 1, 2, or 3 where 0 is normal stools, 1 is loose stools, 2 is moderate diarrhea, and 3 is severe diarrhea
Mentions: We then assessed in a proof-of-concept study whether CR3294, at the dose (20 mg/kg) that significantly decreased mucosal damage, also reduced the incidence and/or severity of diarrhea in mice exposed to 5-FU. Nearly all mice (13 out of 15) receiving 5-FU and vehicle developed diarrhea starting from day 4. The number of mice without diarrhea for the entire study was 3-fold higher in the group treated with CR3294 than in vehicle-treated animals. Moreover, pretreatment with CR3294 reduced the cumulative symptom score by 50% (Fig. 3). Moderate-to-severe diarrhea (grade 2–3) was more frequent in the vehicle-treated group than in the group treated with CR3294 (13 vs. 4 observations; nearly 70% reduction). Similar results were found when we analyzed the 7-day study period during which all mice were alive (Fig. 4). Statistical analysis showed a significant difference (P < 0.05, Mann–Whitney rank sum test) between the two groups in the median diarrhea score.Fig. 3

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