RETINOID-INDUCED SUPPRESSION OF SQUAMOUS-CELL DIFFERENTIATION IN HUMAN ORAL SQUAMOUS-CELL CARCINOMA XENOGRAFTS (LINE-1483) IN ATHYMIC NUDE-MICE

Retinoids are promising agents for therapy of squamous cancers. In vit ro, retinoids decrease expression of differentiation markers in head a nd neck squamous carcinoma cells. Little information is available on e ffects of retinoids on head and neck squamous carcinoma cell xenograft growth in vivo. To address this issue, head and neck squamous carcino ma cells (line 1483) were established as xenografts in nude mice. Cont rol tumors grew rapidly with doubling times of 4-6 days to mean volume s of 1696 mm(3) after 24 days. Histological analyses indicated the for mation of well-differentiated squamous carcinoma cells exhibiting pron ounced stratification (basal and suprabasal cells) and keratinization (keratin pearls) with abundant stroma. Cytokeratin 19 expression was r estricted to the basal cell layers, and cytokeratin 4 expression was a bundant in suprabasal cells. Mice were treated daily with 30 mg/kg 9-c is retinoic acid, 20 mg/kg all-trans-retinoic acid, or 60 mg/kg 13-cis retinoic acid by p.o. gavage on a schedule of 5 days/week over 4 week s. Low micromolar (1.48-3.67 mu M) and nanomolar (200-490 nM) concentr ations of 9-cis retinoic acid and all-trans-retinoic acid were measure d in plasmas and xenografts, respectively, 30 min after dosing. Retino id treatment produced a marked suppression of the squamous cell differ entiation of tumor cells manifest by decreased keratinization, loss of stratification, and accumulation of basal cells. This was accompanied by large decreases in the number of CK4-positive cells and concomitan t increases of CK19-positive cells. Retinoic acid receptor-beta expres sion was also increased by 2.9-9.7-fold after chronic retinoid treatme nt. 9-cis retinoic acid and all-trans-retinoic acid decreased tumor vo lumes by 23 +/- 5 (SE) and 19 +/- 3%, respectively (P less than or equ al to 0.05); 13-cis retinoic acid was inactive. These retinoids did no t decrease the rate of exponential tumor growth but increased the late nt period until exponential growth began. These studies demonstrate th at retinoids do not universally decrease tumor growth but profoundly s uppress squamous cell differentiation in vivo in this xenograft model.