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Effect of 4-Hydroxyphenylretinamide on Human Cervical Epithelial and Cancer Cell Lines

Anne-Thérèse Vlastos, MD

Li Yang, PhD

Jian Wang, MD

Molly Brewer, DVM, MD

Department of Obstetrics, Gynecology and Reproductive Sciences, The University of Texas Medical School at Houston, Houston, Texas; Départment de Gynécologie et Obstérique, Hôpitaux Universitaires de Genève, Geneva, Switzerland; Experimental Laboratory Medicine, Division of Pathology and Laboratory Medicine, Department of Gynecologic Oncology and Center for Biomedical Engineering, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Michele Follen, MD, PhD

Department of Obstetrics, Gynecology and Reproductive Sciences, The University of Texas Medical School at Houston, Houston, Texas; Départment de Gynécologie et Obstérique, Hôpitaux Universitaires de Genève, Geneva, Switzerland; Experimental Laboratory Medicine, Division of Pathology and Laboratory Medicine, Department of Gynecologic Oncology and Center for Biomedical Engineering, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; Center for Biomedical Engineering, Unit 193, The University of Texas M. D. Anderson Cancer Center, 1515 M. D. Anderson Boulevard, Houston, TX 77030 mfollen{at}mdanderson.org

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.

Key Words: Cervical intraepithelial neoplasia • squamous intraepithelial lesions • human papillomavirus • cervical cancer • 4-hydroxyphenylretinamide

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