Comparing the effects of atamestane, toremifene and tamoxifen alone and in combination, on bone, serum lipids and uterus in ovariectomized rats.
Complete estrogen blockade remains under investigation as a means to optimize anti-estrogen therapy in breast cancer thus both the efficacy and end-organ toxicities are of interest with combinations. We hypothesized that a steroidal aromatase inhibitor (AI) atamestane (ATA) alone, and in combination with the anti-estrogens tamoxifen (TAM) or toremifene (TOR) would have beneficial effects in ovariectomized (OVX) rats on key end-organ functions including bone and lipid metabolism and on the endometrium. Significant positive effects on bone were noted with ATA, TOR, TAM, ATA+TOR, or ATA+TAM. TOR, TAM, ATA+TOR, or ATA+TAM caused significant decreases in serum cholesterol and low-density lipoprotein cholesterol whereas ATA had no effect. Uterine weight and epithelium lining height were not increased by ATA but were by TOR and TAM. No significant differences were found in the key parameters outlined above between OVX rats given TOR and ATA+TOR, or TAM and ATA+TAM. Our data show that ATA in combination with TOR or TAM is equivalent to TOR or TAM alone in terms of end-organ effects within a range of clinically relevant doses. Further studies of combinations of AIs with anti-estrogens on end-organ function are merited.
Breast Cancer Research, Massachusetts General Hospital Cancer Center, Breast Cancer Disease Program, Dana Farber/Harvard Cancer Center, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA. pgoss@partners.org
Paul E
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Haiqing
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D000735:Androstenedione / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D047072:Aromatase Inhibitors / Q000494:pharmacology; D001835:Body Weight; D015519:Bone Density; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D002986:Clinical Trials as Topic; D019245:Compressive Strength; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D005269:Femur / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008055:Lipids / Q000097:blood*; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000378:metabolism; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D013629:Tamoxifen / Q000494:pharmacology*; D017312:Toremifene / Q000494:pharmacology*; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects*
D047072:Aromatase Inhibitors; D050071:Bone Density Conservation Agents; D004965:Estrogen Antagonists; D008055:Lipids; D013629:Tamoxifen; D000735:Androstenedione; C048751:atamestane; D017312:Toremifene