ADDITIVE INHIBITORY EFFECTS OF RETINOIDS AND INTERFERON-ALPHA ON THE GROWTH OF HUMAN CERVICAL-CARCINOMA CELLS - LACK OF ASSOCIATION WITH HPV STATUS OR RETINOID RECEPTOR EXPRESSION

The combination of 13-cis retinoic acid (13CRA) and interferon-alpha ( IFN-alpha) has shown marked antitumor activity against locally advance d cervical cancer in vivo. To begin to explore the mechanism and poten tial of the efficacy of this combination, the sensitivity of 9 cervica l carcinoma cell lines to the growth inhibitory effects of these agent s was examined after 1 to 7 days of treatment. IFN-alpha (100 U/ml) al one exerted variable effects. SiHa cell line was very sensitive showin g 75% inhibition. ME180, CaSki, MS751, and C33-A cell lines were moder ately inhibited (30-45% inhibition), and C41, HeLa, and HT-3 cell line s were poorly responsive (20% inhibition or less). 13CRA (10(-9) to 10 (-6) M) alone also caused variable growth inhibitory effect. ME180, Si Ha, and HT-3 exhibited considerable inhibition (IC(50)s of 9x10(-8), 4 x10(-8), and 7x10(-8) M, respectively and maximal inhibition of 80%, 7 9%, and 83% at 10(-6) M) and the other cell lines showed minor respons es (20-45% inhibition at 10(-6) M). ME180, MS751, C41, and HeLa demons trated additive growth inhibitory effects of 13CRA and IFN-alpha where as the other 4 cell lines showed no additive effects. All the cell lin es expressed mRNAs for the nuclear retinoid receptors (RARs and RXRs) RAR-alpha, RAR-gamma, and RXR-alpha, however, RAR-beta mRNA was detect ed only in ME180, MS751, C4I, and CaSki. Treatment with retinoic acid increased RAR-alpha level in C4I, HT-3, and CaSki; RAR-beta in HT-3; a nd RAR-gamma in HT-3 and C4I cells. IFN-alpha treatment did not exert any effect on the level of mRNA for any of the retinoid receptors in a ny of the cell lines or on the level of HPV18 E6 and E7 mRNA in HeLa c ells. Treatment with the combination of RA and IFN-alpha did not affec t the level of receptor mRNAs differently than RA alone did. There app eared to be no correlation between the responses of the cells to these agents and the presence or type of nuclear retinoid receptor, human p apillomavirus, or mutant p53 in the cells.