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Obstetrics & Gynecology 2001;98:332-340
© 2001 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Retinoic Acid and Interferon-{alpha} Effects on Cell Growth and Differentiation in Cervical Carcinoma Cell Lines

Masatoshi Yokoyama, MD, Yoshifumi Nakao, MD, Tsuyoshi Iwasaka, MD, Alan Pater, PhD and Hajime Sugimori, MD

From the Department of Obstetrics and Gynecology, Saga Medical School, Saga, Japan; and the Division of Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada.

Address reprint requests to: Masatoshi Yokoyama, MD, Department of Obstetrics and Gynecology, Saga Medical School, Saga 849-8501, Japan; E-mail: yokoyam1{at}post.saga-med.ac.jp.

OBJECTIVE: To investigate and compare the efficacy of all-trans retinoic acid (RA) and/or interferon-{alpha} (IFN-{alpha}) on premalignant and malignant models of cervical cancer.

METHODS: Cell growth rate was examined after treatment for 4, 7, and 10 days with RA and/or IFN-{alpha} of human papillomavirus type 18 (HPV 18)-immortalized endo- and ectocervical cells, nontransformed serum-adapted cells, transformed cells, three adenocarcinoma, and three squamous cell carcinoma cell lines. The effect on epithelial differentiation by RA and IFN-{alpha} was examined in organotypic culture. Induction of apoptosis was examined by modified terminal transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) and DNA fragmentation.

RESULTS: Cell growth rate was inhibited by RA, 84–96% in HPV 18-immortalized endocervical cells, SiHa, and ME180, 0% in OMC-4, and 18–62% in other cell lines; and by IFN-{alpha} about 75% in SiHa and ME180 and 14–40% in the other cell lines. Combining RA and IFN-{alpha} increased the antiproliferative effect in premalignant cell lines and some cancer cell lines except OMC-4, SiHa, and HT-3. In rafts, RA treatment reversed human endocervical cell metaplasia and HPV 18-immortalized endo- and ectocervical cell dysplastic epithelial differentiation. Interferon-{alpha}, not RA, treatment of HPV 18-immortalized endo- and ectocervical cells induced apoptosis.

CONCLUSION: Cell growth inhibition by treatment with RA, IFN-{alpha}, and their combination differentially depends on treatment type and time, cell origin, cell line, and oncogenic state. In a premalignant model of cervical carcinoma, RA reduces dysplastic differentiation and IFN-{alpha} induces apoptosis. These data confirm that these treatments may be effective for preventing or treating premalignant cervical lesions.




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