RETINOIC ACID RECEPTOR-BETA EXPRESSION AND GROWTH-INHIBITION OF GYNECOLOGIC CANCER-CELLS BY THE SYNTHETIC RETINOID N-(4-HYDROXYPHENYL) RETINAMIDE

Background: The synthetic retinoid N-(4-hydroxyphenyl) retinamide (4HP R) can inhibit the growth of tumor cells. Preliminary results from a c linical trial suggest that 4HPR may reduce ovarian cancer incidence. W e examined the growth-inhibitory effects of 4HPR on gynecologic cancer cell lines in vitro and the role of retinoid receptors in modulating this effect. Methods: Twelve human gynecologic cancer cell lines (the ovarian cell lines-A224, AD10, UCI 101, UCI 107, SKOV3, 222, CP70, ML3 B, and ML5; the cervical cell lines-HT3 and ME180; and the endometrial cell line-Hec 1A were tested for sensitivity to 4HPR (by assaying cel l proliferation rates). Cel electrophoretic analysis of DNA fragmentat ion was used to measure programmed cell death (apoptosis), Specific re tinoid receptor (retinoic acid receptor [RAR] and retinoid X receptor) messenger RNA (mRNA) levels were measured by northern blot hybridizat ion, AD10 cells were stably transfected with human RAR beta complement ary DNA, and the effect of 4HPR on cell proliferation was examined, Re sults: 4HPR inhibited the growth of all 12 cell lines, but to varying degrees; IC50 values (i.e., concentrations that inhibit proliferation by 50%) ranged from 0.3 to 9 mu M. Following 4HPR treatment, ovarian c ancer cells that were sensitive to 4HPR (222, CP70, and UCI 101; IC50 <3 mu M) contained higher levels of RAR beta transcripts than more res istant cells (AD10, ME180, Hec 1A, and A224; IC50 greater than or equa l to 3 mu M) (2.8-fold; two-sided P = .006), Anchorage-independent gro wth of transfected AD10 cells expressing high levels of RAR beta was t otally abolished, even in the absence of 4HPR; transfectants expressin g low levels of RAR beta exhibited lower levels of anchorage-independe nt growth and grew more slowly in the presence of 4HPR than control un transfected AD10 cells. Conclusion: 4HPR inhibited the proliferation o f ovarian cancer cells lit vitro; RAR beta expression appeared to be a ssociated with this effect.