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, Paul E.; Qi, Shangle; Hu, Haijun; Cheung, Angela M.

doi:10.1007/s10549-006-9381-y

Cited by 19 publications

(13 citation statements)

References 42 publications

(29 reference statements)

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“…As monotherapy TOR has a significant and equivalent stimulatory effect on uterine epithelium as TAM. These monotherapy findings are consistent with published studies in this rat model [24][25][26][27][28][29][30].…”

Section: Discussionsupporting

confidence: 93%

See 1 more Smart Citation

Comparing the effects of atamestane, toremifene and tamoxifen alone and in combination, on bone, serum lipids and uterus in ovariectomized rats

Goss

2009

The Journal of Steroid Biochemistry and Molecular Biology

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Section: Discussionsupporting

confidence: 93%

“…Unlike similar effects in this model with the steroidal AI exemestane, our previous study [30] showed these bone preserving effects are not blocked by the androgen receptor blocker flutamide [33] and thus appear to be non-androgenic [4,30,34,35]. The mechanism of bone preserving effects of ATA remains unexplained.…”

Section: Discussionmentioning

confidence: 68%

Comparing the effects of atamestane, toremifene and tamoxifen alone and in combination, on bone, serum lipids and uterus in ovariectomized rats

Goss

2009

The Journal of Steroid Biochemistry and Molecular Biology

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“…2) is currently in two phase III clinical trials, including a recently completed study of atamestane with toremifene as compared with letrozole for advanced breast cancer and a study of toremifene with or without atamestane versus letrozole in women with metastatic breast cancer. In preclinical experiments, atamestane with or without toremifene was found to have fewer side-effects than letrozole, with favorable effects on bone, serum, and uterine markers [81].…”

Section: Aromatase Inhibition and Breast Cancermentioning

confidence: 96%

Natural Products as Aromatase Inhibitors

Balunas¹,

Su²,

Brueggemeier³

et al. 2008

ACAMC

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With the clinical success of several synthetic aromatase inhibitors (AIs) in the treatment of postmenopausal estrogen receptor-positive breast cancer, researchers have also been investigating also the potential of natural products as AIs. Natural products from terrestrial and marine organisms provide a chemically diverse array of compounds not always available through current synthetic chemistry techniques. Natural products that have been used traditionally for nutritional or medicinal purposes (e.g., botanical dietary supplements) may also afford AIs with reduced side effects. A thorough review of the literature regarding natural product extracts and secondary metabolites of plant, microbial, and marine origin that have been shown to exhibit aromatase inhibitory activity is presented herein. Keywordsaromatase inhibitors; natural products; breast cancer; botanical dietary supplements BREAST CANCERWorldwide breast cancer estimates included over one million incident cases and almost 400,000 deaths in the year 2000 [1,2]. In the United States, over 178,000 women were expected to be diagnosed with breast cancer in 2007 with over 40,000 deaths occurring from the disease [3]. In developed countries, mortality from breast cancer has recently begun to decline, primarily due to earlier detection and improved treatments [4,5]. Breast cancer is thought to be a result of inherited genetic predisposition (e.g., mutations in genes such as BRCA-1, p53, PTEN/MMAC1, and/or ATM) and/or environmental factors (e.g., radiation exposure, dietary factors, alcohol consumption, hormonal exposure) [2,6,7]. Numerous genetic mutations are necessary for breast cancer development and progression including the acquisition of the capabilities for self-sufficiency in growth signals, insensitivity to anti-growth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis, known collectively as the "hallmarks of cancer" [8].Numerous molecular targets have been identified as playing a significant role in breast cancer development and progression. Estrogens and the estrogen receptors (ERs) are widely NIH Public Access Author ManuscriptAnticancer Agents Med Chem. Author manuscript; available in PMC 2011 April 12.Published in final edited form as:Anticancer Agents Med Chem. 2008 August ; 8(6): 646-682. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript recognized to play an important role in the development and progression of breast cancer, making estrogens and the ERs widely studied molecular targets [9][10][11][12]. Two of the endogenous estrogens found in humans include estradiol and estrone. In pre-menopausal women, estrogens are produced primarily through conversion of androgens in the ovaries while estrogen production in postmenopausal women occurs in only peripheral tissues [13,14]. Estrogens have various effects throughout the body, including positive effects on the brain, bone, heart, liver, and vagina, with negative effects such as increased risk...

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“…Once tumors reached a diameter of ∼7 mm, the mice were randomized to receive daily concentrations of vehicle [10% N-methyl-pyrollidone (NMP)/90% polyethylene glycol (PEG300, Fluka)], PTK/ZK (25, 50, or 100 mg/kg), letrozole (1 mg/kg), or PTK/ZK (50 mg/kg) in combination with letrozole (1 mg/kg). The dose ranges used had previously been described (11,16).…”

Section: Human Tumor Xenograftsmentioning

confidence: 99%

Biological Evidence for Dual Antiangiogenic-Antiaromatase Activity of the VEGFR Inhibitor PTK787/ZK222584In vivo

Banerjee

A’Hern

Detre

et al. 2010

Clinical Cancer Research

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Purpose: Targeting vascular endothelial growth factor (VEGF) and estrogen receptor signaling pathways concomitantly may enhance benefit in estrogen receptor-positive breast cancer. We had shown previously that the VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 (PTK/ZK) is a competitive aromatase inhibitor in vitro. Here we investigated (a) whether PTK/ZK shows both antiangiogenic and antiaromatase inhibitory properties in vivo, and (b) whether the combination of PTK/ZK and letrozole is superior to letrozole alone.Experimental Design: Estrogen-dependent human breast cancer cells engineered to express aromatase (MCF7 AROM 1 and BT474 AROM) were used. Mice were treated with vehicle, PTK/ZK (25, 50, or 100 mg/kg), letrozole, or PTK/ZK in combination with letrozole.Results: In MCF7 AROM 1 tumors, all treatments induced growth suppression and were associated with a reduction in cell turnover index, a composite measurement of both proliferation and apoptosis. PTK/ZK significantly reduced vessel density. Whereas letrozole caused tumor regression, PTK/ZK stabilized tumor volumes. The growth suppressive and antiangiogenic effects of PTK/ZK were confirmed in BT474 AROM xenografts. The addition of PTK/ZK did not enhance the growth-suppressive effects of letrozole. However, PTK/ZK decreased progesterone receptor (PgR) and TFF1 expression and uterine weight, indicating that PTK/ZK decreases 17β-estradiol (E2) signaling in vivo.Conclusion: The VEGF receptor inhibitor PTK/ZK showed effects on E2-dependent gene expression consistent with aromatase inhibition as well as antiangiogenesis in xenograft models of breast cancer. The combination with letrozole was not superior to letrozole alone. Overall, these results provide further support for a potential therapeutic approach of dual inhibition of VEGF and E2 signaling using a single agent. Clin Cancer Res; 16(16); 4178-87. ©2010 AACR.

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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

Cited by 19 publications

References 42 publications

Comparing the effects of atamestane, toremifene and tamoxifen alone and in combination, on bone, serum lipids and uterus in ovariectomized rats

Comparing the effects of atamestane, toremifene and tamoxifen alone and in combination, on bone, serum lipids and uterus in ovariectomized rats

Natural Products as Aromatase Inhibitors

Biological Evidence for Dual Antiangiogenic-Antiaromatase Activity of the VEGFR Inhibitor PTK787/ZK222584In vivo

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