Anti-proliferative effect of retinoids and interferon-alpha-2a on vaginal cell lines derived from squamous intra-epithelial lesions.
A panel of retinoids (all-trans-, 13-cis-, 19-cis retinoic acid and acitretin), and interferon-alpha-2a was tested for the capacity to modulate the proliferation of UT-DEC-1 (HPV-33-positive) and UT-DEC-2 (HPV-16-positive) cell lines derived from vaginal intra-epithelial neoplasias (VAIN). At concentrations 10(-6) to 10(-8) M, all retinoids inhibited the growth of early-passage UT-DEC cell lines, but also of normal vaginal keratinocytes and fibroblasts. The inhibition was significantly reduced in late-passage UT-DEC cells. The effect on proliferation was essentially equal for all retinoids in high (1.8 mM)-Ca2+ medium, but decreased markedly in low (0.09 mM)-Ca2+ medium. Interferon-alpha-2a at 1000 IU/ml had an additive growth-inhibitory effect in the low- and in the high-Ca2+ medium. No consistent decrease in HPV E6-E7 mRNA levels could be associated either with retinoid or with interferon effect in either cell line. The expression of TGFbeta1 and TGFbeta2 mRNA increased 2- to 3-fold by 10(-6) M 13-cis-RA treatment in early- and in late-passage cells of both cell lines. TGFbeta1 at 0.1 to 1.0 ng/ml also inhibited the proliferation of both cell lines, and was more effective at early passage, but the inhibition was not dependent on calcium concentration. Neutralizing anti-TGFbeta antibodies partially relieved the proliferation inhibition by 13-cis-RA. The results show that the calcium-associated regulation of growth by the tested retinoids was seen in normal vaginal cells and in early pre-neoplastic cells, but was significantly reduced in cells with higher-grade phenotype, while also suggesting that the loss of responsiveness to retinoids and TGFbeta may play a role in the progression of squamous intra-epithelial neoplasia.
Medicity Research Laboratory, Department of Gynecology and Obstetrics, Turku University, Finland. sakari.hietanen@utu.fi
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D017255:Acitretin / Q000494:pharmacology*; D002278:Carcinoma in Situ / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D015474:Isotretinoin / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D011994:Recombinant Proteins; D012176:Retinoids / Q000494:pharmacology*; D014212:Tretinoin / Q000031:analogs & derivatives / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014621:Vagina / Q000166:cytology*; D014625:Vaginal Neoplasms / Q000473:pathology*
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D012176:Retinoids; D014212:Tretinoin; D015474:Isotretinoin; D017255:Acitretin