1.Phase III, double-blind, controlled trial of atamestane plus toremifene compared with letrozole in postmenopausal women with advanced receptor-positive breast cancer.
Goss P1, Bondarenko IN, Manikhas GN, Pendergrass KB, Miller WH Jr, Langecker P, Blanchett D. J Clin Oncol. 2007 Nov 1;25(31):4961-6.
PURPOSE: To compare time to progression (TTP) with a steroidal aromatase inhibitor (AI) atamestane (ATA) combined with toremifene (TOR; complete estrogen blockade) versus letrozole (LET) in receptor-positive advanced breast cancer (ABC).
2.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.
Goss PE1, Qi S, Hu H, Cheung AM. Breast Cancer Res Treat. 2007 Jul;103(3):293-302. Epub 2006 Oct 25.
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.
3.Toremifene-atamestane; alone or in combination: predictions from the preclinical intratumoral aromatase model.
Sabnis GJ1, Macedo L, Goloubeva O, Schayowitz A, Zhu Y, Brodie A. J Steroid Biochem Mol Biol. 2008 Jan;108(1-2):1-7. Epub 2007 Sep 7.
Since most breast cancers occur in postmenopausal women and are hormone dependent, we developed a model system that mimics this situation. In this model, tumors of human estrogen receptor (ER) positive breast cancer cells stably transfected with aromatase (Ac-1) are grown in immune-compromised mice. Using this model we have explored a number of therapeutic strategies to maximize the antitumor efficacy of antiestrogens (AEs) and aromatase inhibitors (AIs). This intratumoral aromatase xenograft model has proved accurate in predicting the outcome of several clinical trials. In this current study we compared the effect of an AE toremifene and steroidal AI atamestane, alone or in combination, on growth of hormone-dependent human breast cancer. We have also compared toremifene plus atamestane combination with tamoxifen in this study. The growth of Ac-1 cells was inhibited by tamoxifen, toremifene and atamestane in vitro with IC(50) values of 1.
4.Comparing the effects of atamestane, toremifene and tamoxifen alone and in combination, on bone, serum lipids and uterus in ovariectomized rats.
Goss PE1, Qi S, Hu H. J Steroid Biochem Mol Biol. 2009 Feb;113(3-5):233-40. doi: 10.1016/j.jsbmb.2009.01.005. Epub 2009 Jan 20.
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.