ANTIPROLIFERATIVE EFFECT OF RETINOIDS AND INTERFERON-ALPHA-2A ON VAGINAL CELL-LINES DERIVED FROM SQUAMOUS INTRAEPITHELIAL LESIONS

A panel of retinoids (all-trans-, 13-cis-, 19-cis retinoic acid and ac itretin), and interferon-alpha-2a was tested for the capacity to modul ate the proliferation of UT-DEC-1 (HPV-33-positive) and UT-DEC-2 (HPV- 16-positive) cell lines derived from vaginal intra-epithelial neoplasi as (VAIN), At concentrations 10(-6) to 10(-8) M, all retinoids inhibit ed the growth of early-passage UT-DEC cell lines, but also of normal v aginal 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 lev els could be associated either with retinoid or with interferon effect in either cell line. The expression of TGF beta 1 and TGF beta 2 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. TGF beta 1 at 0.1 to 1.0 ng/ ml also inhibited the proliferation of both cell lines, and was more e ffective at early passage, but the inhibition was not dependent on cal cium concentration. Neutralizing anti-TGF beta antibodies partially re lieved the proliferation inhibition by 13-cis-RA, The results show tha t the calcium-associated regulation of growth by the tested retinoids was seen in normal vaginal cells and in early pre-neoplastic cells, bu t was significantly reduced in cells with higher-grade phenotype, whil e also suggesting that the loss of responsiveness to retinoids and TGF beta may play a role in the progression of squamous intra-epithelial neoplasia. Int. J. Cancer 78:338-345, 1998. (C) 1998 Wiley-Liss, Inc.