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 of precancerous 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 required for a 50% growth inhibition within 5 days were determined.
Results:The agent 4-HPR inhibited the growth of cervical carcinoma cell lines and HPV-immortalized cell lines in a dose and time-dependent fashion. Doses of 5 and 10 μM were more effective than 1 μM. 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.
Conclusions:The agent 4-HPR is active against several cervical cancer cells lines and HPV-immortalized cervical epithelial cell lines. These findings are consistent with data from other laboratories studying other organ systems. This study helps establish a relevant biologically active dose for clinical trials in the cenvix, one corresponding to the 5 and 10-μM tissue doses.
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