Effect of 4-Hydroxyphenyiretinamide on Human

OBJECTIVE: Topical trans-retinoic acid treatment produced a statistically significant regression of cervical intraepithelial neoplasia (CIN) 2, but not CIN 3, in trials. A promising oral retinoid, 4-hydroxyphenyl-retinamide (4-HPR) induced apoptosis through non-retinoic acid-mediated pathways and is being studied in National Cancer Institute phase II trials in several organ sites. We studied the effects of 4-HPR on cervical cancer cell lines and on cervical epithelial cell lines immortalized by human papillomavirus (HPV). METHODS: Four immortalized cervical epithelial cell lines (in vitro models ofprecancerous CIN lesions) and nine cervical carcinoma cell lines were studied. The growth inhibitory effect of 4-HPR was tested in monolayer culture and in semisolid medium, and concentrations requiredfor a 50 % growth inhibition within 5 days were determined. RESULTS: The agent 4-HPR inhibited thegrowth ofcervical carcinoma cell lines and HPV-immortalized cell lines in a dose- and time-dependentfashion. Doses of 5 and 10 pxM were more effective than 1 pkM. The C33A cell line was most sensitive to 4-HPR, and HeLa and HT3 were the least sensitive. Of the HPV-immortalized cell lines, Z132, an HPV-16 immortalized cell line, was sensitive; the HPV 18-immortalized cell lines (Z173, Z183, and TCL- 1) were not, although they were sensitive when grown in colonies