Letrozole

Letrozole is a third generation inhibitor of aromatase with IC50 of 0.07-20 nM.

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Letrozole Chemical Structure

Letrozole Chemical Structure
Molecular Weight: 285.3

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Product Information

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Product Description

Biological Activity

Description Letrozole is a third generation inhibitor of aromatase with IC50 of 0.07-20 nM.
Targets Aromatase [1]
IC50 0.07 nM-20 nM
In vitro Letrozole potently inhibits aromatase derived from a variety of different sources including human placental microsomes, particulate fractions of human breast cancer, rat ovarian microsomes, MCF-7 cells transfected with aromatase (MCF-7Ca), JEG-3 human choriocarcinoma cells , CHO cells, hamster ovarian tissue, and particulate fractions of human breast cancer with IC50 of 11, 2, 7, 0.07, 0.07, 1.4, 20 and 0.8 nM. In the non-cellular systems, the IC50 of letrozole is calculated to be 1-13 nM. [1] Letrozole maximally inhibits estradiol production in vitro in LH-stimulated hamster ovarian tissue at 0.1 μM with an IC50 of 0.02 μM and does not significantly affect progesterone production up to 350 μM. In ACTH-stimulated rat adrenal tissue in vitro, aldosterone production is inhibited by with an IC50 of 210 μM. [2] Letrozole inhibits growth of the MCF-7 epithelial breast cancer cells in a dose-dependent way with IC50 of 1 nM. Inhibition can be observesed even at the very low concentrations tested (0.1 nM). Treatment of normal MCF-12A epithelial cells with letrozole did not affect their growth even when high letrozole concentrations (100 nM) or prolonged culture times. Letrozole (10 nM) significantly suppressed the stimulatory effects of 4-androstene-3,17-dione (100 nM) or testosterone (100 nM) on MCF-7 cell proliferation. Concurrent administration of 17-β-estradiol with letrozole (10 nM) decreased the stimulatory effect of the enzymatic activity of MMP-2 and - 9 released by estradiol. [3]
In vivo Letrozole inhibits aromatase in vivo with ED50 of 1-3 μg/kg p.o.. [2] Letrozole displays anti-endocrine effects. Letrozole inhibits androstenedione-induced uterine hypertrophy in immature rats with ED50 of 1-3 μg/kg. In the adult female rat, Letrozole (0.3-1 mg/kg daily p.o., 14 days) completely interrupts ovarian cyclicity and reduces uterine weight and serum estradiol (E2) concentrations to a similar extent to that seen after ovariectomy. [1] Letrozole induces dose-dependent regression of estrogen-dependent, 9,10-dimethylbenz-a-anthracene (DMBA)-induced mammary tumors in adult female rats. The ED50 for Letrozole is determined to be 10 - 30 µg/kg/day, with complete inhibition at a daily dose of 10 µg/day. [4] Letrozole produces dose-dependent inhibition of tumor growth of MCF-7 cells transfected with human aromatase gene (MCF-7Ca) implanted athymic nude mice, with complete inhibition at 20 mg/kg per day p.o.. [5]
Features

Protocol(Only for Reference)

Kinase Assay: [6]

Human placental aromatase activity The assay is performed in a total volume of 1 mL at 37 ℃. Unless otherwise noted, the incubation mixture contains 11 nM [4- 14C] androstene-3, 17-dione ([4- 14C]A), 24 mM NADPH (tetrasodium salt Type III), the appropriate concentrations of the desired inhibitor, and 120 μg of microsomal protein. The (4- 14C)A is added as a solution in 1.7% ethanol in 0.05 M potassium phosphate buffer (pH 7.4), so that the final concentration of ethanol does not exceed 0.02% (v/v). The reaction is started by the addition of enzyme and stopped after 20 min by the addition of 7 vol of ethyl acetate. The mixture is agitated on a vortex mixer and centrifuged at 600 g for 5 min. The aqueous phase is re-extracted with 7 vol of ethyl acetate, and the combined extracts are evaporated to dryness using an Evapo-Mix. Over 99% of the radio- active of [4- 14C] added is recovered using this extraction system. The residue obtained is dissolved in 150 μL acetone, and 100 μL aliquots are chromatographed for 65 min on thin-layer plates precoated with silica gel 60 using ethyl: acetate: isooctane (140:60, v/v; system A) or toluene: chloroform: methanol (70:140:20; system B). The radioactive zones of the plate are located with a Berthold LB 2760 thin-layer scanner. The radioactive estradiol (E2) and estrone (E1) neaks are identified by comparison with authentic standards. The corresponding bonding band of silica gel is transferred to vials containing 10 mL of scintillation fluid, and counted with a 6880 Liquid Scintillation system.

Cell Assay: [3]

Cell lines Human breast cancer cells MCF-7
Concentrations ~100 nM
Incubation Time 1 days
Method Cells are seeded in duplicate at 5,000 to 10,000 cells per well in 24-well plates. The day after plating, different concentrations of Letrozole are added. At the end of incubation, cells are trypsinizated and placed in Isotone solution and counted immediately using a Coulter particle-counter.

Animal Study: [5]

Animal Models Human breast carcinoma xenografts MCF-7 with human aromatase gene (MCF-7Ca)
Formulation 0.5% (w/v) solution of carboxymethylcellulos
Dosages 20 mg/kg/day
Administration orally administered by gavage once every 2 days
Solubility 0.5% CMC, 10 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Haynes BP, et al. J Steroid Biochem Mol Biol, 2003, 87(1), 35-45.

[2] Bhatnagar AS, et al. J Steroid Biochem Mol Biol, 1990, 37(6), 1021-1027.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2015-04-18)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02344472 Not yet recruiting Metastatic Breast Cancer Prof. W. Janni|University of Ulm April 2015 Phase 3
NCT02128360 Not yet recruiting Infertility Sheba Medical Center March 2015 --
NCT02297438 Recruiting Breast Neoplasms Pfizer March 2015 Phase 3
NCT02401425 Recruiting Complete Miscarriage Ain Shams University March 2015 Phase 2|Phase 3
NCT02405156 Recruiting Miscarriage Ain Shams University March 2015 Phase 2|Phase 3

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Chemical Information

Download Letrozole SDF
Molecular Weight (MW) 285.3
Formula

C17H11N5

CAS No. 112809-51-5
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms CGS 20267
Solubility (25°C) * In vitro DMSO 57 mg/mL (199.78 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 0.5% CMC 10 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name  4,​4'-​(1H-​1,​2,​4-​triazol-​1-​ylmethylene)​bis-benzonitrile

Research Area

Customer Product Validation (2)


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Rating
Source Endocrinology 2013 154, 2296-307. Letrozole purchased from Selleck
Method Immunohistochemistry
Cell Lines LNCaP tumor xenografts
Concentrations 10 mg/kg body weight
Incubation Time 2 d
Results Effect of aromatase inhibitor letrozole on cellular proliferation marker Ki-67 expression in LNCaP tumor xenografts. A, Ki-67 immunostaining in transverse sections of xenograft tumors from C, C+T, C+T+D, C+T+L, and C+T+D+L mice 2 days after testosterone replacement. Panel B, Quantification of Ki-67–positive cells in LNCaP tumors at day 2 post testosterone replacement. Error bars represent SEM. Number of animals in each group is shown in parentheses. ***, P <.0001.

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Rating
Source PLoS One 2014 9(1), e85581. Letrozole purchased from Selleck
Method
Cell Lines aP2-Cre/ERα<sup>flox/flox</sup> mice
Concentrations 10 mg/kg
Incubation Time 17 days
Results To analyze if inhibition of endogenous estrogen synthesis via the aromatase enzyme would reverse hydrometra, we treated aP2-Cre/ERαflox/flox (n = 5) and ERαflox/flox (n = 5) mice with the aromatase inhibitor Letrozole or vehicle. Mice were 10 weeks old at the start of the treatment, at which stage all aP2-Cre/ERαflox/flox mice displayed clear visual signs of hydrometra. Importantly, Letrozole treatment reversed visual signs of hydrometra in aP2-Cre/ERαflox/flox (n = 3) mice within one week of treatment. When the mice were sacrificed after 17 days of treatment, uteri appeared grossly normal in Letrozole-treated mice while the vehicle-treated mice presented a severe hydrometra phenotype.

Product Use Citation (4)

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