Retinoic acid and interferon-alpha effects on cell growth and differentiation in cervical carcinoma cell lines.
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.


CONCLUSIONS
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.
Yokoyama
M
M
Department of Obstetrics and Gynecology, Saga Medical School, Saga, Japan. yokoyam1@post.saga-med.ac.jp
Nakao
Y
Y
Iwasaka
T
T
Pater
A
A
Sugimori
H
H
D000230:Adenocarcinoma / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002584:Cervix Uteri / Q000166:cytology / Q000187:drug effects; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D027383:Papillomaviridae; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000473:pathology* / Q000821:virology
D000970:Antineoplastic Agents; D016898:Interferon-alpha; D014212:Tretinoin