The chemopreventive agents 4-HPR and DFMO inhibit growth and induce 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.


METHODS
Primary cultures of human uterine leiomyomas and matched normal myometrium were established from hysterectomy specimens. After treatment with 4-HPR, DFMO, or the combination 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.


CONCLUSIONS
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.
Broaddus
Russell R
RR
Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Tex, USA. rbroaddu@mdanderson.org
Xie
Susu
S
Hsu
Ching-Ju
CJ
Wang
Jian
J
Zhang
Sui
S
Zou
Changping
C
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D000518:Eflornithine / Q000494:pharmacology*; D005260:Female; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D007889:Leiomyoma / Q000473:pathology* / Q000503:physiopathology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014594:Uterine Neoplasms / Q000473:pathology* / Q000503:physiopathology*
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53; D017313:Fenretinide; D000518:Eflornithine