Chemopreventive Action of Mesalazine on Colorectal Cancer: a Pilot Study for an "in Vivo" Evaluation of the Molecular Effects on β-catenin Signaling Pathway.

Colorectal Cancer Clinical Trial

Official title:

Azione Chemiopreventiva Della Mesalazina Sul Cancro Del Colon-retto: Studio Pilota Per la Valutazione Degli Effetti Molecolari "in Vivo" Sulla Via di Segnalazione Proliferativa Della β-catenina (Official Title in Italian Language)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02077777
• Other study ID #: MES-CT 01
• Status: Completed
• Phase: Phase 2
• First received: February 28, 2014
• Last updated: December 1, 2016
• Start date: October 2012
• Est. completion date: June 2016

Study information

• Verified date: December 2016
• Source: SOFAR S.p.A.
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: National Monitoring Centre for Clinical Trials - Ministry of Health
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to obtain an "in vivo" confirmation that mesalazine induces the gene expression of μ-protocadherin and other related genes in the colon mucosa, as demonstrated in some "in vitro" experiments. .

Description:

Pilot Trial, single-blind, parallel group on biopsy specimens of healthy colon mucosa in patients with precancerous lesions of the colon and rectum (adenomas) treated with mesalazine.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 21
• Est. completion date: June 2016
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients with precancerous colorectal lesions (polypoid or nonpolypoid adenomas) that needs of an endoscopic exam of control after 3 months from the removal of the lesions (determined on the basis of the morphological and histological characteristics of the lesions and of the removal technique)

• Ability and willingness to adhere to study regimen

• Written informed consent

The following inclusion criteria was deleted according to Amendment n. 01 approved by the Ethical Committee on 19/dec/2014:

• diverticular disease/diverticular colitis;

The rationale of this change is that the presence of diverticular disease/diverticular colitis does not contribute to the definition of the trial primary end-points and represents a critical point during the patient selection with an impact on duration and conduction of the study.

Exclusion Criteria:

• Patients under therapy with Aspirin (>100 mg/die) or other FANS

• Inflammatory bowel disease (IBD)

• Hypersensitivity to Mesalazine.

• Pregnant or nursing (lactating) women

• Patients who belonging to the category n. 4 of the ASA physical status classification system

• contraindications to mesalazine therapy

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms

Intervention

Drug:
• Mesalazine
Mesalazine cpr 800 mg t.i.d. for 3 months

Locations

Country	Name	City	State
Italy	Istituti Ospitalieri di Cremona	Cremona

Sponsors (1)

Lead Sponsor	Collaborator
SOFAR S.p.A.

Country where clinical trial is conducted

Italy, 

References & Publications (7)

Brown JB, Lee G, Managlia E, Grimm GR, Dirisina R, Goretsky T, Cheresh P, Blatner NR, Khazaie K, Yang GY, Li L, Barrett TA. Mesalamine inhibits epithelial beta-catenin activation in chronic ulcerative colitis. Gastroenterology. 2010 Feb;138(2):595-605, 605.e1-3. doi: 10.1053/j.gastro.2009.10.038. — View Citation

Gushima M, Hirahashi M, Matsumoto T, Fujita K, Fujisawa R, Mizumoto K, Nakabeppu Y, Iida M, Yao T, Tsuneyoshi M. Altered expression of MUTYH and an increase in 8-hydroxydeoxyguanosine are early events in ulcerative colitis-associated carcinogenesis. J Pathol. 2009 Sep;219(1):77-86. doi: 10.1002/path.2570. — View Citation

Losi L, Parenti S, Ferrarini F, Rivasi F, Gavioli M, Natalini G, Ferrari S, Grande A. Down-regulation of µ-protocadherin expression is a common event in colorectal carcinogenesis. Hum Pathol. 2011 Jul;42(7):960-71. doi: 10.1016/j.humpath.2010.10.009. — View Citation

Lyakhovich A, Gasche C. Systematic review: molecular chemoprevention of colorectal malignancy by mesalazine. Aliment Pharmacol Ther. 2010 Jan 15;31(2):202-9. doi: 10.1111/j.1365-2036.2009.04195.x. Review. — View Citation

Obtulowicz T, Swoboda M, Speina E, Gackowski D, Rozalski R, Siomek A, Janik J, Janowska B, Ciesla JM, Jawien A, Banaszkiewicz Z, Guz J, Dziaman T, Szpila A, Olinski R, Tudek B. Oxidative stress and 8-oxoguanine repair are enhanced in colon adenoma and carcinoma patients. Mutagenesis. 2010 Sep;25(5):463-71. doi: 10.1093/mutage/geq028. — View Citation

Parenti S, Ferrarini F, Zini R, Montanari M, Losi L, Canovi B, Ferrari S, Grande A. Mesalazine inhibits the beta-catenin signalling pathway acting through the upregulation of mu-protocadherin gene in colo-rectal cancer cells. Aliment Pharmacol Ther. 2010 Jan;31(1):108-19. doi: 10.1111/j.1365-2036.2009.04149.x. — View Citation

Velayos FS, Terdiman JP, Walsh JM. Effect of 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and metaanalysis of observational studies. Am J Gastroenterol. 2005 Jun;100(6):1345-53. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Molecular analysis of gene expression levels of µ-protocadherin and other related proteins	Molecular analysis (quantitative RT-PCR) of gene expression levels of µ-protocadherin, protocadherin 19, protocadherin 24, cadherin E, TCF7L2, TCF4, c-myc, Cyclin D1, p21waf1, VEGF, CD44, Met, KLF4 e CEBP-a and comparison of the levels assessed at the end of the treatment period with the baseline.	3 months	No
Secondary	Evaluation of protein expression level of µ-protocadherin, Ki-67, Caspase-3 and Histone H2AX?, evaluation of DNA oxidative damage and intra-mucosal concentration of 5-Acetylsalicylic acid	These parameters will be examined using molecular analysis of the oxidation and depurination levels of the DNA and chromatographic analysis of the intra-mucosal concentration of 5-Acetylsalicylic acid, in biopsies of normal mucosa of the colon taken before and after the treatment of patients with 5-Acetylsalicylic acid: quantification of the percentage of cells expressing the following proteins by immunohistochemical analysis: µ-protocadherin, Ki-67, Caspase-3 and Histone H2AX?; quantification of number of AP sites per 100000 DNA bp; quantification of nanograms di 8-OhdG (8-hydroxyguanine) per micrograms of DNA	3 months	No