Preclinical evidence for therapeutic efficacy of selective estrogen receptor modulators for uterine leiomyoma.
OBJECTIVE
Uterine leiomyoma are the most common gynecologic neoplasm and a primary cause of hysterectomy in premenopausal women. Preclinical studies were conducted in the Eker rat model to investigate the potential efficacy of selective estrogen receptor modulators (SERMs) as therapeutic agents for this tumor.


METHODS
Twelve-month-old Eker rats were randomized into five treatment arms including tamoxifen, placebo, LY 326315, vehicle, and no treatment. Additional animals received ovariectomy or sham surgery at 4 months of age to determine the effect of ovarian ablation on tumor development. The study was terminated after 2 to 4 months of treatment, and tumor incidence, size, proliferative and apoptotic indices were determined. Size and incidence data were subjected to chi-square analysis. One-way analysis of variance and Fisher's least significant difference tests were used to compare proliferative and apoptotic indices.


RESULTS
Ovariectomy virtually ablated leiomyoma development, indicating that these tumors were dependent on ovarian hormones for growth and development. Treatment with tamoxifen or raloxifene analog LY 326315 reduced leiomyoma incidence by 40-60% and reduced the size of remaining tumors. The effect of SERMs on leiomyomas was mediated by a decrease in cell proliferation without a decrease in apoptotic index.


CONCLUSIONS
SERMs have been shown to be therapeutically efficacious against breast cancer and to reduce tumor incidence in women at increased risk for this disease. The present data indicate that therapeutic efficacy may also be extended to uterine leiomyoma and demonstrate the utility of this animal model for preclinical studies to identify new therapeutic modalities.
Walker
C L
CL
University of Texas M. D. Anderson Cancer Center-Science Park, Research Division, Smithville, Texas, USA. cwalker@odin.mdacc.tmc.edu
Burroughs
K D
KD
Davis
B
B
Sowell
K
K
Everitt
J I
JI
Fuchs-Young
R
R
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D004195:Disease Models, Animal; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D007889:Leiomyoma / Q000188:drug therapy* / Q000473:pathology; D010052:Ovariectomy; D010919:Placebos; D020849:Raloxifene Hydrochloride / Q000627:therapeutic use; D051381:Rats; D011922:Rats, Mutant Strains; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use*; D013629:Tamoxifen / Q000627:therapeutic use; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000473:pathology
D004965:Estrogen Antagonists; D010919:Placebos; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D020849:Raloxifene Hydrochloride