Differential inhibitory effects on human endometrial carcinoma cell growthof luteinizing hormone-releasing hormone analogues

In addition to its function as a key hormone in the regulation of the pitui tary-gonadal axis, luteinizing hormone-releasing hormone (LHRH) probably al so affects various extrapituitary tissues. LHRH binding sites and in vitro antiproliferative effects of LHRH analogues have been reported in human end ometrial cancer. The effects of the LHRH agonist leuproreline and LHRH anta gonist antide were studied on the cell growth, DNA synthesis, and cell cycl e distribution of the human endometrial cancer cell lines HEC-1A and HEC-1B by the sulforhodamine B (SRB) method, [H-3]thymidine assay incorporation, and propidium iodide DNA staining, respectively. In the presence of 1.0-100 mu M leuproreline the proliferation of HEC-1A cells was significantly redu ced as early as 3 days after drug exposure, with a minimum growth value of 69.9 +/- 3.6% (mean +/- SE) at the highest concentration tested (100 mu M). Similar antiproliferative effects were obtained following a 6-day treatmen t with the LHRH antagonist antide. Also, inhibitory effects on [H-3]thymidi ne incorporation into the DNA of the HEC-1A cell line were noted after a 6- day exposure to both LHRH analogues, in the above-mentioned concentration r ange. Cell cycle analysis of HEC-1A cells cultured in the presence of 10 mu M leuproreline and antide showed a slight accumulation of cells in the G(0 )/G(1) phase, while the proportions of cells in the S and G(2)/M phases con comitantly decreased. No significant effects on proliferation, DNA synthesi s, and cell cycle distribution were observed in HEC-1B cells with either le uproreline or antide (up to 100 and 10 mu M, respectively) after a 6-day ex posure. Both Northern blot analysis and reverse transcription polymerase ch ain reaction failed to detect expression of mRNA for the LHRH receptor in b oth HEC-1A and HEC-1B cell lines. In addition, the LHRH analogues did not a ffect the intracellular free calcium concentration, indicating that the cla ssic signal transduction for LHRH is absent or impaired in HEC-1A cells. Th e observed direct inhibitory actions on HEC-1A cells support the concept th at the two LHRH analogues may exert biological effects via cellular effecte rs distinct from the "classic" LHRH receptor, Although the mechanism by whi ch these direct actions are produced is still obscure, these results might help to establish the basis for new approaches to the therapy of endometria l cancer, (C) 1998 Academic Press.