Subscribe to RSS
Evaluation of genotoxicity related to oral methylene blue chromoendoscopyTRIAL REGISTRATION: Single-center, non-randomized, prospective trial NCT02295774 at clinicaltrials.gov
submitted 27 November 2017
accepted after revision 16 April 2018
15 June 2018 (online)
Background An oral formulation of methylene blue with colonic delivery (MB-MMX) has been developed to increase detection of colorectal polys during colonoscopy. Traditionally, there have been safety concerns regarding DNA damage when methylene blue is exposed to white light. The aim of this study was to evaluate DNA damage in colonic mucosa after MB-MMX chromoendoscopy.
Methods This was an open-label phase II safety study to assess for genotoxicity on colorectal biopsies of patients undergoing two sequential colonoscopies before and after an oral dose of 200 mg MB-MMX added to their bowel prep. Analysis of a biomarker of double-stranded DNA breaks, γH2AX, was performed on biopsy specimens.
Results Ten patients were included in the study. The mean expression of γH2AX ± 95 % confidence intervals of the 50 biopsies before and after MB-MMX administration were 0.58 ± 0.08 and 0.62 ± 0.09, respectively (P = 0.24). None of the analyzed samples showed excess positive γH2AX expression, confirming the absence of DNA damage on biopsies after methylene blue exposure. No deaths or serious adverse events occurred.
Conclusions An oral dose of 200 mg of MB-MMX did not result in any detectable DNA damage.
- 1 Rahmi G, Lecomte T, Malka D. et al. Impact of chromoscopy on adenoma detection in patients with Lynch syndrome: a prospective, multicenter, blinded, tandem colonoscopy study. Am J Gastroenterol 2015; 110: 288-298
- 2 Huneburg R, Lammert F, Rabe C. et al. Chromocolonoscopy detects more adenomas than white light colonoscopy or narrow band imaging colonoscopy in hereditary nonpolyposis colorectal cancer screening. Endoscopy 2009; 41: 316-322
- 3 Subramanian V, Mannath J, Ragunath K. et al. Meta-analysis: the diagnostic yield of chromoendoscopy for detecting dysplasia in patients with colonic inflammatory bowel disease. Aliment Pharmacol Ther 2011; 33: 304-312
- 4 Subramanian V, Mannath J, Hawkey CJ. et al. High definition colonoscopy vs. standard video endoscopy for the detection of colonic polyps: a meta-analysis. Endoscopy 2011; 43: 499-505
- 5 ASGE Technology Committee, Wong Kee Song LM, Adler DG et al. Chromoendoscopy. Gastrointest Endosc 2007; 66: 639-649
- 6 Kamiński MF, Hassan C, Bisschops R. et al. Advanced imaging for detection and differentiation of colorectal neoplasia: ESGE Guideline. Endoscopy 2014; 46: 435-449
- 7 Laine L, Kaltenbach T, Barkun A et al; SCENIC Guideline Development Panel. SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease. Gastrointest Endosc 2015; 81: 489-501
- 8 National Institute for Health and Clinical Excellence. NICE clinical guideline 131. Colorectal cancer. The diagnosis and the management of colorectal cancer. 2011 Available from: https://www.nice.org.uk/Guidance/CG131 Accessed: 30 April 2018
- 9 National Toxicology Program. NTP technical report on the toxicology & carcinogenesis studies of methylene blue trihydrate (CAS No. 72220-79-3) in F344/ rats and B6C3F1 mice (Gavage Studies). Natl Toxicol Program Tech Rep Ser 2008; 540: 1-224
- 10 Davies J, Burke D, Olliver JR. et al. Methylene blue but not indigo carmine causes DNA damage to colonocytes in vitro and in vivo at concentrations used in clinical chromoendoscopy. Gut 2007; 56: 155-156
- 11 Olliver JR, Hardie LJ, Dexter S. et al. DNA damage levels are raised in Barrett's oesophageal mucosa relative to the squamous epithelium of the oesophagus. Biomarkers 2003; 8: 509-521
- 12 US Food and Drug Administration. FDA drug safety communication: serious CNS reactions possible when methylene blue is given to patients taking certain psychiatric medications. Available from: http://www.fda.gov/Drugs/DrugSafety/ucm263190.htm . Accessed: 8 May 2018
- 13 Sedelnikova OA, Bonner WM. γH2AX in cancer cells. A potential biomarker for cancer diagnostics prediction and recurrence. Cell Cycle 2006; 5: 2909-2913
- 14 Porcedda P, Turinetto V, Brusco A. et al. A rapid flow cytometry test based on histone H2AX phosphorylation for the sensitive and specific diagnosis of ataxia telangiectasia. Cytometry 2009; 6: 508-516
- 15 Banath JP, Olive PL. Expression of phosphorylated histone H2AX as a surrogate of cell killing by drugs that create DNA double-strand breaks. Cancer Res 2003; 63: 4347-4350
- 16 Zhang JH, Chung TD, Oldenburg KR. A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J Biomol Screen 1999; 4: 67-7338
- 17 National Toxicology Program. Executive summary of safety and toxicity information: methylene blue. CAS Number 61-73-4/7220-79-3. 1990. Available from: https://ntp.niehs.nih.gov/ntp/htdocs/chem_background/exsumpdf/methyleneblue_508.pdf Accessed: 30 April 2018
- 18 Repici A, Di Stefano AF, Radicioni MM. et al. Methylene blue MMX tablets for chromoendoscopy. Safety tolerability and bioavailability in healthy volunteers. Contemp Clin Trials 2012; 33: 260-267
- 19 Kuo LJ, Yang LX. γH2AX – A novel biomarker for DNA double-strand breaks. In Vivo 2008; 22: 305-310
- 20 Kiesslich R, Neurath MF. Chromoendoscopy in inflammatory bowel disease. Gastroenterol Clin North Am 2012; 41: 291-302