Steroidal aromatase inhibitorWe've noticed that you're using an ad blocker Our content is brought to you free of charge because of the support of our advertisers. To continue enjoying our content, please turn off your ad blocker. Anastrozole Arimidexletrozole Femaraand exemestane Aromasin are members of the third generation of aromatase inhibitors that has now replaced aminoglutethimide Cytadrenthe steroidal vs nonsteroidal ai, and tamoxifen Nolvadex as the hormonal therapy of choice in estrogen-receptor-positive, postmenopausal, metastatic breast cancer. This article will review the role of aromatase in the pathogenesis steroidal vs nonsteroidal ai breast cancer and the results of recent studies that have established the role of its inhibitors in estrogen-receptor-positive breast cancer. We will also briefly outline the rationale and design of ongoing studies.
Nonsteroidal and Steroidal Aromatase Inhibitors in Breast Cancer | Cancer Network
Steroidal aromatase inhibitors are a class of drugs that are mostly used for treating breast cancer in postmenopausal women. High levels of estrogen in breast tissue increases the risk of developing breast cancer and the enzyme aromatase is considered to be a good therapeutic target when treating breast cancer due to it being involved in the final step of estrogen biosynthetic pathway and also its inhibitation will not affect production of other steroids.
Aromatase Inhibitors are classified into two categories based on their structure, nonsteroidal and steroidal; the latter resemble the structure of androstenedione. The foundation was the center point of collaboration of many scientists interested in reproduction, neurophysiology and steroid biochemistry. One of the foundations work was the understanding of the mechanism of conversion of androgens to estrogens.
The group worked on understanding the biosynthesis and metabolism of steroids that are produced by adrenal glands , testes and ovaries. Andre Meyer later hypothesized that the aromatization of androstenedione was enzymatic and this was proven in the s with the purification of aromatase. Harry Brodie , a chemist, joined the WFEB group and started working on understanding steriochemistry of hydrogen elimination at the C-1 position during aromatization.
His mechanistic studies led him to recognizing the therapeutic potential of targeting aromatase, in the early s he started the development of selective aromatase inhibitors. After the Brodies demonstrated the reduction of estrogen levels in rodents and its biological efficacy with regression of rat mammary tumors, Angela Brodie went to Rome in the fall to give a presentation about her research.
At the presentation was Charles Coombes a medical oncologist who expressed his interests in conducting a clinical trial with 4-hydroxy-androstenedione 4-OH-A to treat breast cancer. Due to the unfavourable characters of 4-OH-A, poor oral bio-availability and unfavourable metabolism, a group led by E. Di Salle and P. Lombardi at Farmitalia-Carlo Erba part of Pfizer started working on a new selective aromatase inhibitor.
The group designed, synthesized and evaluated a new novel steroid, exemestane. Exemestane went through clinical trials in the s and received FDA approval in , marketed as Aromasin. Indication for exemestane is advanced breast cancer in postmenopausal women, where the cancer has progressed following tamoxifen therapy.
Exemestane is the first oral aromatase inactivator. Clinical use of steroidal aromatase inhibitors today is more or less limited to exemestane. Use of formestane Lentaron is very limited and in some countries it is not used anymore.
Formestane has been superseded by newer and better inhibitors with better oral availability and fewer side effects, exemestane and the newer generation of nonsteroidal aromatase inhibitors. Because aromatase catalyses the final step in estrogen conversion, inhibiting it does not have any effect on synthesis of other steroids except estrogen.
In postmenopausal women the production of estrogen in the ovaries has ceased. The main source of estrogen is therefore aromatization of androgens produced by the adrenal glands. Aromatase inhibitors stops this conversion and lowers the levels of estrogen. Treating breast cancer with aromatase inhibitors is only effective in postmenopausal women because of high levels of aromatase ligands substrate in ovaries of premenopausal women. By inhibiting aromatase in premenopausal women the estrogen levels are reduced for a short time but it leads to activation of the hypothalamus and the pituitary axis which promote gonadotropin secretion that causes rise in estrogen levels by stimulating the ovaries.
A study has shown that cross resistance does not always occur between nonsteroidal aromatase Inhibitors and steroidal aromatase inhibitors. Aromatase Inhibitors have been used to preserve fertility by stimulate ovulation in premenopausal breast cancer survivors. By inhibiting aromatase in premenopausal women the estrogen levels are reduced temporarily which leads to increased gonadotropin secretion and stimulate ovaries and that causes rise in estrogen levels.
Testolactone and formestane are 1st and 2nd generation aromatase inhibitors. Formestane was the first selective aromatase inhibitor that was used for breast cancer treatment but it is not in clinical use today. Exemestane is the only steroidal 3rd generation aromatase inhibitor and it has the advantage over formestane in being more potent and can be administrated orally. Estrogen plays a major part in the stimulation of breast cancer cell proliferation in hormone-dependent breast cancer.
High concentrations of estrogen seem to promote the development of breast cancer. Consequently, two main approaches to control and block the pathological activity of estrogens have been developed. The second focuses on directly inhibiting estrogen production by inhibiting the estrogen synthetase aromatase.
Aromatase is a cytochrome P which catalyzes three consecutive hydroxylation reactions, converting C19 androgens to aromatic C18 estrogens. After gaining electrons from NADPH-cytochrome P reductase, the aromatase converts androstenedione and testosterone to estrone and estradiol , respectively.
The aromatization of androgen is the terminal and rate-limiting step in estrogen synthesis. Recent studies have focused on defining the active site region of the aromatase enzyme and to evaluate the most promising reaction mechanism. Three-dimensional models of the aromatase active region have also been generated, though the exact nature of the structure has not yet been fully defined.
Drugs like exemestane and other steroidal aromatase inhibitors have a steroidal structure that competes with the natural aromatase substrate androstenedione. This renders the steroidal aromatase inhibitors inherently selective. The drugs bound to the catalytic site are often metabolized to intermediates which have much higher affinity for the androgen receptor. The binding of the intermediate metabolite hydroexemestane for the androgen receptor is about times that of the parent compound, exemestane.
Even if all unattached parts of the inhibitor are removed, the enzyme activity of the aromatase can only be restored by new enzyme synthesis. There is no need for continued presence of the drug to maintain inhibition, which in turn reduced the chance of toxic adverse effects to the patient. Planarity of the A ring is very important for the affinity of the compounds to aromatase. As can be seen in table 1 , where compounds 2 and 3 show substantial inhibition and also have the same stereochemical requirements.
These differences in the structure of AIs show the importance of planarity in the A ring for interaction with the active site of aromatase. Important aspect to the binding properties of the compounds is the stereochemistry in the C-5 section where the position of the hydrogen atom can be in alfa or beta positions pointing up or down. These results indicate the importance of a correct angle between the A and B-ring junction for better binding to the active site of aromatase.
Compound 9 combined the D-ring structure of testolactone and the A-ring structure of formestane but had considerably lower inhibition of aromatase than formestane.
C-4 region is important for the interaction of AIs with the binding region and hydrophilic bonds such as hydroxyl or carbonyl bonds in that position can improve interaction with aromatase. This is likely the cause of two polar amino acids in the active site and underlines the importance of hydrophilic groups in the steroids for better binding properties. The synthesis of steroidal aromatase inhibitors is done with various methods, they all have in common that they are synthesized from a starting point that is the base structure of steroids.
With various methods there a various starting point of synthesis, f. The synthesis of Formestane from testosterone is a facile three step synthesis, as shown in figure 2. Step 2 is hydroxylation of androstene-3,dione with OsO4 followed by step 3 with alkaline dehydration of the resultant diols to give formestane.
The synthesis of exemestane also consists of three steps, as shown in figure 3. A mixture of From Wikipedia, the free encyclopedia. European Journal of Medicinal Chemistry. Clin Oncol R Coll Radiol. Int J Womens Health. Are there differences between steroidal and nonsteroidal aromatase inhibitors and do they matter? Annals of the New York Academy of Sciences. Aromatase Inhibitors for Breast Cancer: Anastrozole Exemestane Fadrozole Formestane Letrozole.
Mixed mechanism of action: Danazol Gestrinone Androstenedione immunogens: Androvax androstenedione albumin Ovandrotone albumin Fecundin.