Squamous cell carcinoma (SCC) of the human esophagus has a multifactorial e
tiology involving several environmental and/or genetic factors. Current mod
alities of therapy for this disease offer poor survival and cure rates. Alt
hough a number of approaches could be undertaken to reduce the occurrence o
f esophageal SCC, including changes in lifestyle and improved nutrition, su
ch approaches are not easily implemented. Chemoprevention offers a viable a
lternative that is likely to be effective against this disease. Clinical in
vestigations in areas of high incidence of esophageal SCC have shown that p
rimary chemoprevention of this disease is feasible, if potent inhibitors ar
e identified. Studies in the Fischer 344 rat model of nitrosamine-induced t
umorigenesis have proven valuable in understanding the biology of esophagea
l SCCs and help identify surrogate end-point biomarkers and putative agents
that can be useful in human chemoprevention studies. Several compounds tha
t inhibit tumor initiation by suspected human esophageal carcinogens have b
een identified using this model. These include diallyl sulfide, isothiocyan
ates and several polyphenolic compounds. Novel biomarkers, including nuclea
r/nucleolar morphometry using computer-assisted image analysis of preneopla
stic lesions, have been developed to measure efficacy of chemopreventive ag
ents against esophageal SCC. The identification of single agents that inhib
it the progression of dysplastic lesions, however, has proven difficult. Re
sults from a food-based approach suggest that the use of freeze-dried berry
preparations can affect both initiation and promotion/progression of esoph
ageal SCC in an animal model. These observations provide valuable informati
on for future studies on chemoprevention of cancers of the esophagus in a c
linical setting. Given the complex etiology of esophageal SCC, it is felt t
hat the most effective chemoprevention strategies would include agents that
reduce mutational events associated with carcinogen exposure in combinatio
n with agents that inhibit the progression of intraepithelial dysplasia to
invasive cancer.