The primary objective of this study is to identify small molecules that target critical
transcription factors for potential application in the
chemoprevention of
esophageal cancer. Specificity
proteins (Sp) play a critical role in the growth and
metastasis of several
malignancies including
esophageal cancer. Researchers at the M. D. Anderson
Cancer Center Orlando
Cancer Research Institute have reported previously that
tolfenamic acid (TA) inhibits
cancer cell proliferation and
tumor growth through the degradation of Sp1, Sp3, and Sp4. We evaluated the chemopreventive properties of TA against esophageal
tumorigenesis in
N-nitrosomethylbenzylamine (NMBA)-induced murine
tumor model. Fischer-344 rats were treated with NMBA (0.5 mg/kg s.c. 3 times a week) for 5 weeks to initiate the
tumor formation, and then treated with 50 mg/kg TA from week 6 through week 25.
Tumor incidence,
tumor multiplicity (number of
papilloma per rat), and
tumor volume were evaluated after 25 weeks. All rats in the control group that received only NMBA developed lesions (100% incidence), while the TA-treated group showed significantly lower (33%)
tumor incidence and
tumor multiplicity. Furthermore, the
tumor volume was significantly diminished in the TA-treated group when compared with the control group. Using small molecules such as TA to target key
transcription factors associated with
tumorigenesis for the prevention of esophageal
malignancies is a new and promising strategy. Results of the current study provide evidence that TA, when given orally after
tumor initiation, can significantly suppress
tumorigenesis induced by carcinogenic
nitrosamines in rats. These appealing results demonstrate that TA may potentially serve as an effective chemopreventive agent in patient populations vulnerable to
esophageal cancer.