IN VITRO RADIOSENSITIZATION OF HUMAN CERVICAL CARCINOMA CELLS BY COMBINED USE OF 13-CIS-RETINOIC ACID AND INTERFERON-α2a

Abstract

Background: Significant antitumor activity has been reported with the combined use of 13-cis-retinoic acid (cRA) and interferon-a2a (IFN-a) in the treatment of advanced-stage cervical cancers and skin cancers. Since IFN-a has been shown to be a modest radiation enhancer for selected malignant tumor cells and the cytotoxic activity is more enhanced by combining cRA and IFN-a, we hypothesized that the exposure of selected human carcinoma cells to combined cRA and IFN-a would render the cells highly radiosensitive. Methods and Materials: Two human cervical carcinoma cell lines, ME-180 and HeLa-S3, were chosen for the present study because of the different characteristics of the retinoic acid receptor status of the cell lines. To demonstrate the effects of combined cRA and IFN-a treatment on radiation response, we exposed the cells to cRA, IFN-a, or a combination of the drugs for 72 h before radiation. Experiments were carried out at minimally cytotoxic concentrations of the drug for radiation studies. End points of the study were cell growth inhibition and clonogenic ability of the single-plated cells. Effects of cRA and IFN-a on radiation response were quantitatively analyzed by constructing the radiation cell survival curves of ME-180 and HeLa cells. Results: ME-180 cells exhibited varying degrees of cytotoxicity with cRA and IFN-a, while HeLa cells showed no toxic effects with the same treatment. Combined treatment of cRA and IFN-a produced an additive cytotoxic effect in ME-180 cells. Radiosensitization was minimal when ME-180 cells were treated with either cRA or IFN-a before radiation. When ME-180 cells were exposed to 10 mM cRA for 48 h and 1000 U/ml IFN-a for 24 h prior to radiation, there was a significant enhancement in radiation-induced cell killing; the dose modification factor was 2.1 6 0.9 at the 1% cell-survival level. On the other hand, HeLa-S3 cells exhibited no increased cytotoxicity or radiation enhancement under the same experimental conditions. Conclusion: The present data provide a radiobiological basis for using cRA and IFN-a as a combination radiosensitizer in selected human carcinoma cells. © 1998 Elsevier Science Inc. 13-cis-Retinoic acid, Interferon-a2a, Radiosensitization, Retinoic acid receptor.