The synthetic retinobenzoic
acid RE-80 was evaluated for its potential as an inductor of
tumor cell differentiation and as a chemopreventive agent. A minimally toxic dose of
RE-80 in vitro produced morphologic changes typical differentiation in epidermal
tumor cell colonies. Indirect immunofluorescence indicated induction of a differentiation-associated
keratin of internal stratified epithelia, K13, and inhibition of the differentiation-associated epidermal
keratin K1. Cultured cells were skin-grafted to athymic nu/nu mice to evaluate
RE-80 effects on early stage malignant progression in vivo. When
tumors had grown to 3 to 4 mm in diameter, mice were treated by
intraperitoneal injection with
RE-80 (67 micrograms, 170 mmol, i.p., two times per week) or vehicle (100 microliters 20%
ethanol).
Papillomas (benign) and moderately differentiated
squamous cell carcinomas were reduced in volume about 4-fold by
RE-80 treatment. Larger, poorly differentiated
squamous cell carcinomas were unaffected.
RE-80 resulted in a lower proportion of proliferative cells (detectable by
bromodeoxyuridine incorporation) and a higher proportion of moderately to well differentiated
tumors after 40 days of treatment compared with control
tumors, which were mainly poorly differentiated
squamous cell carcinomas. K13 induction in vitro was correlated with response to
retinoid in vivo. Induction of differentiation may be mechanism of the response to
RE-80 in vivo since
carcinoma cells expressing K13 did not incorporate
bromodeoxyuridine and were on a terminal pathway.