The effects of atamestane and toremifene alone and in combination compared with letrozole on bone, serum lipids and the uterus in an ovariectomized rat model.
We compared the effects of atamestane (ATA) and toremifene (TOR) alone and in combination, with letrozole (LET) on bone, serum lipids and the uterus in ovariectomized (OVX) rats after 16 weeks of treatment. Compared to OVX controls lumbar vertebral and femoral BMD as well as mechanical strength and trabecular bone volume were significantly greater in animals given ATA, TOR or ATA + TOR. The effects of ATA were not reversed by the androgen receptor blocker, flutamide (FLT). Serum cholesterol, low-density lipoprotein cholesterol and triglycerides were reduced by TOR and ATA + TOR whereas they remained unchanged in animals receiving ATA, ATA + FLT, and LET. The uterine epithelium in OVX animals was equally stimulated by TOR and ATA + TOR and unaffected by ATA or LET. Intact animals had significant atrophy of the uterine epithelium when receiving ATA. In summary, TOR alone or in combination with ATA had a predictable stimulatory effect on bone and the uterine epithelium while reducing key parameters of lipid metabolism. In contrast, ATA but not LET had an unexpected stimulatory effect on the OVX rat's bone and this was not reversed by the anti-androgen FLT leaving this finding unexplained for now. ATA is distinct from LET on end-organ function and this favorable profile makes clinical testing of this steroidal aromatase inhibitor of interest in the clinical setting.
Goss
Paul E
PE
Breast Cancer Research, Massachusetts General Hospital Cancer Center, Breast Cancer Disease Program, Dana Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA 02114, USA. pgoss@partners.org
Qi
Shangle
S
Hu
Haiqing
H
Cheung
Angela M
AM
D000735:Androstenedione / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D000077289:Letrozole; D008055:Lipids / Q000737:chemistry; D008956:Models, Chemical; D009570:Nitriles / Q000008:administration & dosage*; D009929:Organ Size; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017312:Toremifene / Q000008:administration & dosage*; D014230:Triazoles / Q000008:administration & dosage*; D014599:Uterus / Q000187:drug effects* / Q000473:pathology
D008055:Lipids; D009570:Nitriles; D014230:Triazoles; D000735:Androstenedione; C048751:atamestane; D000077289:Letrozole; D017312:Toremifene