Anastrozole
Encyclopedia
Anastrozole (marketed under the trade name Arimidex by AstraZeneca
) is an aromatase-inhibiting
drug
approved for treatment of breast cancer
after surgery, as well as for metastasis
in both pre and post-menopausal
women. The severity of breast cancer is increased by estrogen
, as sex hormones cause hyperplasia
, and differentiation
at estrogen receptor
sites. Anastrozole works by inhibiting the synthesis of estrogen. The patent on Arimidex by AstraZeneca expired 27 June 2010.
, Alone or in Combination) trial was an international randomised controlled trial of 9366 women with localized breast cancer who received either anastrozole, tamoxifen, or both for five years, followed by five years of follow-up. After more than 5 years the group that received anastrozole had significantly better clinical results than the tamoxifen group. The trial suggested that anastrozole is the preferred medical therapy for postmenopausal women with localized breast cancer that is estrogen receptor
(ER) positive. Another study found that the risk of recurrence was reduced 40%, which also included an increased risk of bone fractures, and that ER negative patients benefited from switching to anastrozole.
enzyme
through competitive inhibition
, inhibits the conversion of androgen
s to estrogen
s in peripheral tissues
(outside the CNS
), and a few CNS sites in various regions within the brain
.
, gynecomastia
, and symptoms of hypogonadism
. It can also contribute to increased risk of stroke, heart attack, chronic inflammation, prostate enlargement and prostate cancer. Some athletes and body builders
will also use anastrozole as a part of their steroid cycle to reduce and prevent symptoms of excess estrogens; gynecomastia
and water retention. Study data suggests dosages of 0.5 mg to 1 mg a day reduce serum estradiol approx. 50% in men, which differs in postmenopausal women.
, or children with pubertal
gynecomastia
. Following the onset of puberty
, the epiphyseal plate
begins to close due to an increased amount of estrogen
production escaping local metabolism
and spreading to the circulatory system
. It is shown to help slow this process, and increase adult height prediction in adolescent males treated with protein-based peptide hormones for the treatment of growth hormone
deficiency.
, not shown on the scheme) with cyanide by treatment with potassium cyanide under phase transfer conditions, affording the dinitrile. Exhaustive methylation with methyl iodide and sodium hydride
leads to the replacement of the more acidic side chain hydrogen
atoms by methyl groups. The treatment with bromine
in the presence of benzoyl peroxide
leads to the formation of the corresponding benzyl bromide. Reaction of that product with 1,2,4-triazole
in the presence of a base
completes the synthesis of the aromatase inhibitor
.
AstraZeneca
AstraZeneca plc is a global pharmaceutical and biologics company headquartered in London, United Kingdom. It is the world's seventh-largest pharmaceutical company measured by revenues and has operations in over 100 countries...
) is an aromatase-inhibiting
Aromatase inhibitor
Aromatase inhibitors are a class of drugs used in the treatment of breast cancer and ovarian cancer in postmenopausal women. AIs may also be used off-label to treat or prevent gynaecomastia in men....
drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
approved for treatment of breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
after surgery, as well as for metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
in both pre and post-menopausal
Menopause
Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...
women. The severity of breast cancer is increased by estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
, as sex hormones cause hyperplasia
Hyperplasia
Hyperplasia means increase in number of cells/proliferation of cells. It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/ benign tumor....
, and differentiation
Grading (tumors)
In pathology, grading is a measure of the cell appearance in tumors and other neoplasms. Some pathology grading systems apply only to malignant neoplasms ; others apply also to benign neoplasms. The neoplastic grading is a measure of cell anaplasia in the sampled tumors arising from the...
at estrogen receptor
Estrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
sites. Anastrozole works by inhibiting the synthesis of estrogen. The patent on Arimidex by AstraZeneca expired 27 June 2010.
Medical uses
The ATAC (Arimidex, TamoxifenTamoxifen
Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...
, Alone or in Combination) trial was an international randomised controlled trial of 9366 women with localized breast cancer who received either anastrozole, tamoxifen, or both for five years, followed by five years of follow-up. After more than 5 years the group that received anastrozole had significantly better clinical results than the tamoxifen group. The trial suggested that anastrozole is the preferred medical therapy for postmenopausal women with localized breast cancer that is estrogen receptor
Estrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
(ER) positive. Another study found that the risk of recurrence was reduced 40%, which also included an increased risk of bone fractures, and that ER negative patients benefited from switching to anastrozole.
Mechanism of action
Anastrozole binds reversibly to the aromataseAromatase
Aromatase is an enzyme responsible for a key step in the biosynthesis of estrogens. It is a member of the cytochrome P450 superfamily , which are monooxygenases that catalyze many reactions involved in steroidogenesis. In particular, aromatase is responsible for the aromatization of androgens into...
enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
through competitive inhibition
Competitive inhibition
Competitive inhibition is a form of enzyme inhibition where binding of the inhibitor to the active site on the enzyme prevents binding of the substrate and vice versa.-Mechanism:...
, inhibits the conversion of androgen
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
s to estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
s in peripheral tissues
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
(outside the CNS
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
), and a few CNS sites in various regions within the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
.
Side effects
Bone weakness has been associated with anastrozole. Women who switched to anastrozole after two years on tamoxifen reported twice as many fractures as those who continued to take tamoxifen (2.1% compared to 1%). Bisphosphonates are sometimes prescribed to prevent the osteoporosis induced by aromatase inhibitors.Usage in men
While officially indicated for women, this drug has proven effective in the off-label use of reducing estrogens (in particular and more importantly, estradiol) in men. Excess estradiol in men can cause benign prostatic hyperplasiaBenign prostatic hyperplasia
Benign prostatic hyperplasia also known as benign prostatic hypertrophy , benign enlargement of the prostate , and adenofibromyomatous hyperplasia, refers to the increase in size of the prostate....
, gynecomastia
Gynecomastia
Gynecomastia or Gynaecomastia, , is the abnormal development of large mammary glands in males resulting in breast enlargement. The term comes from the Greek γυνή gyné meaning "woman" and μαστός mastós meaning "breast"...
, and symptoms of hypogonadism
Hypogonadism
Hypogonadism is a medical term for decreased functional activity of the gonads. Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males...
. It can also contribute to increased risk of stroke, heart attack, chronic inflammation, prostate enlargement and prostate cancer. Some athletes and body builders
Bodybuilding
Bodybuilding is a form of body modification involving intensive muscle hypertrophy. An individual who engages in this activity is referred to as a bodybuilder. In competitive and professional bodybuilding, bodybuilders display their physiques to a panel of judges, who assign points based on their...
will also use anastrozole as a part of their steroid cycle to reduce and prevent symptoms of excess estrogens; gynecomastia
Gynecomastia
Gynecomastia or Gynaecomastia, , is the abnormal development of large mammary glands in males resulting in breast enlargement. The term comes from the Greek γυνή gyné meaning "woman" and μαστός mastós meaning "breast"...
and water retention. Study data suggests dosages of 0.5 mg to 1 mg a day reduce serum estradiol approx. 50% in men, which differs in postmenopausal women.
Usage in children
Anastrozole may be used off-label in children with precocious pubertyPrecocious puberty
As a medical term, precocious puberty describes puberty occurring at an unusually early age. In most of these children, the process is normal in every respect except the unusually early age, and simply represents a variation of normal development. In a minority of children, the early development is...
, or children with pubertal
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
gynecomastia
Gynecomastia
Gynecomastia or Gynaecomastia, , is the abnormal development of large mammary glands in males resulting in breast enlargement. The term comes from the Greek γυνή gyné meaning "woman" and μαστός mastós meaning "breast"...
. Following the onset of puberty
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
, the epiphyseal plate
Epiphyseal plate
The epiphyseal plate is a hyaline cartilage plate in the metaphysis at each end of a long bone...
begins to close due to an increased amount of estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
production escaping local metabolism
Hydroxylation
Hydroxylation is a chemical process that introduces a hydroxyl group into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air...
and spreading to the circulatory system
Circulatory system
The circulatory system is an organ system that passes nutrients , gases, hormones, blood cells, etc...
. It is shown to help slow this process, and increase adult height prediction in adolescent males treated with protein-based peptide hormones for the treatment of growth hormone
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
deficiency.
Chemical synthesis
The synthesis begins with nucleophilic substitution of two benzylic bromides in α,α'-dibromomesitylene (prepared by radical bromination of mesityleneMesitylene
Mesitylene or 1,3,5-trimethylbenzene is an aromatic hydrocarbon with three methyl substituents attached to the benzene ring. It is prepared by distillation of acetone with sulfuric acid or by trimerization of propyne in sulfuric acid, which, in both cases, acts as a catalyst and dehydrating agent....
, not shown on the scheme) with cyanide by treatment with potassium cyanide under phase transfer conditions, affording the dinitrile. Exhaustive methylation with methyl iodide and sodium hydride
Sodium hydride
Sodium hydride is the chemical compound with the empirical formula NaH. It is primarily used as a strong base in organic synthesis. NaH is representative of the saline hydrides, meaning it is a salt-like hydride, composed of Na+ and H− ions, in contrast to the more molecular hydrides such as...
leads to the replacement of the more acidic side chain hydrogen
Hydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...
atoms by methyl groups. The treatment with bromine
Bromine
Bromine ") is a chemical element with the symbol Br, an atomic number of 35, and an atomic mass of 79.904. It is in the halogen element group. The element was isolated independently by two chemists, Carl Jacob Löwig and Antoine Jerome Balard, in 1825–1826...
in the presence of benzoyl peroxide
Benzoyl peroxide
Benzoyl peroxide is an organic compound in the peroxide family. It consists of two benzoyl groups bridged by a peroxide link. Its structural formula is [C6H5C]2O2. It is one of the most important organic peroxides in terms of applications and the scale of its production...
leads to the formation of the corresponding benzyl bromide. Reaction of that product with 1,2,4-triazole
1,2,4-Triazole
1,2,4-Triazole is one of a pair of isomeric chemical compounds with molecular formula C2H3N3, called triazoles, which have a five-membered ring of two carbon atoms and three nitrogen atoms. 1,2,4-Triazole is a basic aromatic heterocycle...
in the presence of a base
Base (chemistry)
For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...
completes the synthesis of the aromatase inhibitor
Aromatase inhibitor
Aromatase inhibitors are a class of drugs used in the treatment of breast cancer and ovarian cancer in postmenopausal women. AIs may also be used off-label to treat or prevent gynaecomastia in men....
.