Abstract 3463: Chemopreventive effect of tolfenamic acid against esophageal tumorigenesis in rats
Authors: Maliakal Pius , Abdelrahim Maen , Baker Cheryl H. , Harrera Luis J. , Ledford Andrea , Basha Md Riyaz 
Published: February 2011

Abstract
Specificity proteins (Sp) play a critical role in the growth and metastasis of several malignancies including esophageal cancer and Sp1 expression is a negative prognostic factor in cancer patients. We have reported previously that tolfenamic acid (TA) inhibits cancer cells proliferation and tumor growth through degradation of Sp1, Sp3 and Sp4. Interestingly TA also significantly inhibited the proto-oncogene c-Met. In the current study the efficacy of TA for prevention of esophageal tumorigenesis in N-nitrosomethylbenzylamine (NMBA)-induced murine tumor model is evaluated.
A well established chemically-induced esophageal tumor model is used in the current studies where Fisher-344 rats were treated with NMBA (0.5 mg/kg s.c.) three times a week for 5 weeks. Two groups of rats received TA (50 mg/kg by oral gavage) three times a week either concurrently with (Weeks 1- 25) or sequentially after (Weeks 6-25) NMBA treatment. Tumor incidence, Tumor multiplicity (number of papilloma per animal) and tumor volume were compared after 25 weeks.
All the rats in the control group which received only NMBA developed tumor lesions. Tumor lesions in the oesophagi were seen as irregular, multiple, exophytic swellings arising from esophageal epithelium, mostly ovoid in shape and oriented along the axis of esophagus. No ulceration was noted in any part of the esophagus. Most of the abnormal oesophagi showed hyperkeratosis and papilloma. TA treated (sequential and concurrent exposure) groups showed significantly lower tumor incidence (33%) and tumor multiplicity when compared to control; however the concurrent TA-exposure group showed the least number of papilloma per rat. Furthermore, the tumor volume was significantly diminished in concurrent TA-exposure group when compared with other control and treatment groups.
Using small molecules such as TA to target key transcription factors associated with tumorigenesis and angiogenesis for the prevention of esophageal malignancies is a new and promising strategy and results of the current study provide evidence that TA when give orally at the time of tumor initiation, promotion and progression can significantly suppress tumorigenesis induced by carcinogenic nitrosamines in rats. Since nitrosamines such as NMBA have been isolated in human gastric juice and often implicated as a causative agent in human esophageal cancer, TA may serve as an effective chemopreventive agent in patient populations vulnerable to esophageal cancer. Seeking in depth knowledge of the molecular mechanisms underlying this beneficial effect of TA, further studies are being carried out presently at our laboratory. Benefits of such exploration are well-warranted to understand better this molecular pathway-targeted prevention of esophageal cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3463.