A Multicenter, randomized, double blind, double dummy, placebo controlled, parallel group, phase II study on the prevention of mucositis by CR3294, orally administered for 5 days in haematological patients receiving high dose chemotherapy followed by autologous stem cell transplantation. - ND

Start Date08 Sep 2010

Sponsor / Collaborator-

100 Clinical Results associated with CR-3294

100 Translational Medicine associated with CR-3294

100 Patents (Medical) associated with CR-3294

Literatures (Medical) associated with CR-3294

01 Oct 2010·Cancer Chemotherapy and PharmacologyQ4 · MEDICINE

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

Q4 · MEDICINE

Article

Author: Albino Bonazzi ; Paolo Garofalo ; Francesco Makovec ; Ornella Letari ; Catherine Booth ; Lucio C. Rovati ; Gianfranco Caselli

PURPOSEGastrointestinal 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.METHODSIn 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.RESULTSCR3294 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.CONCLUSIONSThis 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.

16 Nov 2008·AutophagyQ1 · BIOLOGY

Induction of autophagic cell death by a novel molecule Is increased by hypoxia

Q1 · BIOLOGY

Article

Author: Matteo A. Russo ; Rosanna Beraldi ; Maura Di Vito ; Patrizio Sale ; Bruna Pucci ; Luana Schito ; Corrado Spadafora ; Ornella Letari ; Emanuela Morgante ; Marco Tafani ; Tahira Anwar ; Manuela Indelicato ; Francesco Makovec ; Gianfranco Caselli

Adaptation to hypoxia through activation of the hypoxia inducible factor-1 (HIF-1) is crucial for tumor cells survival. Here we describe the antitumoral effects of the new molecule CR 3294 on tumor cells in the presence of hypoxia. Treatment of the breast carcinoma cell line MDA-MB-231 with CR 3294 in 1% O(2) resulted in an in vivo and in vitro inhibition of tumor growth. CR 3294 induced accumulation of autophagosomes in hypoxic MDA-MB-231 cells as assessed by both transmission electron microscopy (TEM) and the autophagic marker LC3-II. TEM analysis revealed the presence of invaginations of the cytoplasm into the nucleus. Autophagosomes were present in such invaginations. Moreover, CR 3294 inhibited both the DNA binding of HIF-1alpha and VEGF mRNA synthesis. Immunoprecipitation and immunofluorescence studies showed an interaction between LC3 and HIF-1alpha. We next detailed the effect of inhibitors and activators of autophagy on both HIF-1alpha and LC3. In particular, 3 methyladenine (3MA) and wortmannin, two macroautophagic inhibitors, prevented both the decrease of HIF-1alpha protein levels and LC3 processing in cells treated with CR 3294. Bafilomycin and leupeptin, inhibitors of lysosomes, prevented HIF-1alpha decrease without affecting LC3 processing. By contrast, treating hypoxic MDA-MB-231 cells with trifluoperazine (TFP) or serum withdrawal (SW), two activators of autophagy, diminished HIF-1alpha levels and stimulated LC3 processing. These results indicate that activation of the autophagic pathway in hypoxic cells by the new molecule CR 3294, as well as by TFP or SW, can have potentially important implications for cancer treatment.

100 Deals associated with CR-3294

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Diarrhea	Phase 3	-	Rottapharm SpA	-
Inflammatory Bowel Diseases	Phase 3	IT	Rottapharm Madaus GmbH	-
Diarrhea	Phase 2	IT	Rottapharm Madaus GmbH	-
Inflammatory Bowel Diseases	Phase 2	-	Rottapharm SpA	-
Mucositis	Phase 2	IT	Rottapharm Madaus GmbH	-

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