tretinoin and Vaginal-Neoplasms

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.

Topics: Acitretin; Carcinoma in Situ; Cell Division; Cell Line; Dose-Response Relationship, Drug; Female; Fibroblasts; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Keratinocytes; Recombinant Proteins; Retinoids; Tretinoin; Tumor Cells, Cultured; Vagina; Vaginal Neoplasms

Topics: Adult; Antineoplastic Agents; Carcinoma in Situ; Combined Modality Therapy; Female; HIV Infections; Humans; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Tretinoin; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Vaginal Neoplasms; Vulvar Neoplasms