The chemopreventive agents 4-HPR and DFMO inhibit growth and inducee apoptosis in uterine leiomyomas

Objective: This study examined the effects of the chemopreventive agents 4-(N-hydroxyphenyl)retinamide (4-HPR) and alpha-difluoromethylornithine (DFMO) on leiomyoma growth. Study design: Primary cultures of human uterine leiomyomas and matched normal myometrium were established from hysterectomy specimens. After treatment with 4-HPR, DFMO, or the combinatiori 4-HPR plus DFMO, cell growth was analyzed. Apoptosis was quantified with the use of a flow. cytometric terminal deoxynucleotidyl transferase-mediated fluorescein-deoxyuridine-triphosphate nick-end labeling assay. Protein extracts were analyzed with Western blot for p53, p21, and p16. Results: 4-HPR and DFMO inhibited the growth and induced apoptosis of leiomyoma cells, but not matched normal myometrial cells. Both 4-HPR and DFMO caused cells to accumulate at G0/ G1, with a corresponding decrease in the S-phase fraction. Both agents also caused the induction of p53, p21, and p16. Conclusion: The chemopreventive agents 4-HPR and DFMO inhibit leiomyoma cell growth in vitro and induce apoptosis, which implies that retinoids and polyamines are important regulators of leiomyoma growth. (C) 2004 Elsevier Inc. All rights reserved.