An anti-cancer drug impair and repair mechanism (Methotrexate induced mucositis and its prevention in rat model)

9^th Indo Global Summit on Cancer Therapy

November 02-04, 2015 Hyderabad, India

Kasthuri Natarajan and Premila Abraham

Tamil Nadu Dr. M.G.R. Medical University, India

Posters-Accepted Abstracts: J Cancer Sci Ther

Abstract :

Methotrexate (MTX) is widely used as a chemotherapeutic agent for leukemia and other malignancies as well as non-malignant diseases. The efficacy of this drug is often limited by mucositis and intestinal injury which are the major causes of morbidity in children and adults. Despite many studies, the precise mechanism of MTX induced mucositis is still not fully understood. Therefore, currently, there is no definitive prophylaxis or therapeutic treatment for MTX induced mucositis. The present study is aimed to identify the possible mechanism of inflammation and prevention in MTX induced mucositis using a rat model. The experimental rats received three daily intraperitonial injections of 7 mg/kg body weight of methotrexate. Control rats received vehicle alone. For the intervention studies, aminoguanidine was used. Twenty four hours after the final dose of MTX/vehicle, the rats were sacrificed and the small intestine was removed for the studies. Histologically, MTX treated rat small intestine revealed moderate to severe mucosal damage with abscess formation. We found increased levels of iNOS, nitric oxide and superoxide levels which lead to nitrosative stress. Western blot analysis revealed the activation of NFkB and its downstream proteins of inflammatory mechanism and the release of cytochrome c into cytosol, activation of caspases, PARP and DNA fragmentation indicating apoptosis mechanism in response to MTX treatment. Aminoguanidine, a selective iNOS inhibitor, attenuate nitrosative stress, improved MTX induced morphological changes, inhibited NFkB inflammatory pathway and intrinsic apoptotic pathway. Thus, aminoguanidine has a protective role against MTX induced small intestinal damage. In conclusion, these results provide an evidence for the role of oxidative stress, nitrosative stress, activation of inflammatory and apoptosis pathway cause small intestinal damage in the pathogenesis of methotrexate induced mucositis. Thus, aminoguanidine pretreatment deteriorate the methotrexate induced mucositis, reduce side effects and improve efficacy of the drug. This combinational sequence therapy of drugs has a promising output that can be extrapolate to human with further clinical trials.

Biography :

Email: kasthuri.jrf@gmail.com