IN-VITRO RADIOSENSITIZATION OF HUMAN CERVICAL-CARCINOMA CELLS BY COMBINED USE OF 13-CIS-RETINOIC ACID AND INTERFERON-ALPHA-2A

Background: Significant antitumor activity has been reported with the combined use of W-cts-retinoic acid (cRA) and interferon-alpha 2a (IFN -alpha) in the treatment of advanced-stage cervical cancers and skin c ancers. Since IFN-alpha has been shown to be a modest radiation enhanc er for selected malignant tumor cells and the cytotoxic activity is mo re enhanced by combining cRA and IFN-alpha, we hypothesized that the e xposure of selected human carcinoma cells to combined cRA and IFN-alph a would render the cells highly radiosensitive. Methods and Materials: Two human cervical carcinoma cell lines, ME-180 and HeLa-S3, were cho sen for the present study because of the different characteristics of the retinoic acid receptor status of the cell lines. To demonstrate th e effects of combined cRA and IFN-alpha treatment on radiation respons e, we exposed the cells to cRA, IFN-alpha, or a combination of the dru gs for 72 h before radiation. Experiments were carried out at minimall y cytotoxic concentrations of the drug for radiation studies. End poin ts of the study were cell growth inhibition and clonogenic ability of the single-plated cells. Effects of cRA and IFN-alpha on radiation res ponse were quantitatively analyzed by constructing the radiation cell survival curves of ME-180 and HeLa cells. Results: ME-180 cells exhibi ted varying degrees of cytotoxicity with cRA and IFN-alpha, while HeLa cells showed no toxic effects with the same treatment. Combined treat ment of cRA and IFN-alpha produced an additive cytotoxic effect in ME- 180 cells. Radiosensitization was minimal when ME-180 cells were treat ed with either cRA or IFN-alpha before radiation. When ME-180 cells we re exposed to 10 mu M cRA for 48 h and 1000 U/ml IFN-alpha for 24 h pr ior to radiation, there was a significant enhancement in radiation-ind uced cell killing; the dose modification factor was 2.1 +/- 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 experi mental conditions. Conclusion: The present data provide a radiobiologi cal basis for using cRA and LFN-alpha as a combination radiosensitizer in selected human carcinoma cells. (C) 1998 Elsevier Science Inc.