Classes Of Aromatase Inhibitors Research Articles

STEROIDAL AND NONSTEROIDAL AROMATASE INHIBITORS INDUCED DERMATITIS- A CASE REPORT OF CROSS-REACTIVITY

<h3>Introduction</h3> Aromatase inhibitors (AI) are an important adjuvant therapy used in estrogen receptor-positive (ER+) breast cancer. There are two major classes: nonsteroidal (Anastrozole and Letrozole) and steroidal (Exemestane). Cutaneous reactions are treated with discontinuation of the culprit medication and switching to a different class. We describe a unique case of reaction to both classes of AI. <h3>Case Description</h3> 51-year-old woman with history of papillary thyroid carcinoma and ER+ ductal breast carcinoma presented with 2-month history of pruritus without rash after starting Anastrazole. Laboratory studies were normal. She was started on high dose antihistamines with resolution. Two months later pruritus recurred and she developed an erythematous papulovesicular rash all over the trunk. She was treated with oral steroids. Anastrazole was stopped with significant resolution of symptoms within two weeks. She was started on Exemestane with recurrence of rash and pruritus in three weeks. The medication was stopped with resolution and the patient is now doing well on Tamoxifen. <h3>Discussion</h3> Literature on AI induced cutaneous reactions is scarce. Pathogenesis is poorly understood. Symptom onset ranges from 5 days to 6 months. Morphology of cutaneous reactions includes vasculitis, erythema nodosum, and subacute cutaneous lupus. Diagnosis is clinical and treatment includes discontinuation of the offending agent. Topical and systemic immunosuppressants have been used to control symptoms. Switching to a different class of AI is recommended. To our knowledge this is the first patient reported in literature to have reacted to both classes of AI. Further studies are required to determine the best alternative agents for such patients.

Copper Complexes of 8-Aminoquinoline and Uracils as Novel Aromatase Inhibitors

Background: Currently, aromatase inhibitors (AIs) have been developed for the treatment of breast cancers and other estrogen-related conditions. However, searching for more and new classes of AIs is being investigated. 8-Aminoquinoline (8AQ) is an interesting scaffold to be explored. In particular, 8AQ as its mixed ligands (5-nitrouracil, 5Nu and 5-iodouracil, 5Iu) metal complexes are potential compounds to be studied. Keywords: 8-Aminoquinoline, uracil, metal complex, aromatase inhibitor, cytotoxicity, cancer treatment.

Aromatase inhibitors in the breast cancer clinic: focus on exemestane

Breast cancer is the most prevalent type of cancer in women and responsible for significant female cancer-related mortality worldwide. In the Western world, over 80% of breast cancers are hormone-receptor positive for which endocrine therapy is administered. The main anti-estrogen treatments in use consist of selective estrogen-receptor modulators, such as tamoxifen, and third-generation aromatase inhibitors (AIs), such as exemestane, letrozole, and anastrozole. In this review, the focus will lie on exemestane, its clinical use, and its side-effect profile. Exemestane is the only third-generation steroidal AI. Its efficacy as a first-line treatment in metastatic breast cancer has been demonstrated. Therefore, exemestane could be considered a valid first-line therapeutic option, but it also can be used in second-line or further situations. Exemestane is mostly used as part of sequential adjuvant treatment following tamoxifen, but in this setting it is also active in monotherapy. Furthermore, this AI has been studied in the neoadjuvant setting as presurgical treatment, and even as chemoprevention in high-risk healthy postmenopausal women. It may reverse side effects of tamoxifen, such as endometrial changes and thromboembolic disease but may also cause some inconvenient side effects itself. Additionally, there is a lack of total cross-resistance between exemestane and nonsteroidal AIs as far as their anti-tumoral efficacy is concerned; moreover the two classes of AIs display a nontotal overlapping toxicity profile. Taking together, exemestane can be considered as a useful treatment option at all stages of breast cancer.

Aromatase inhibitors and antiepileptic drugs: a computational systems biology analysis

BackgroundThe present study compares antiepileptic drugs and aromatase (CYP19) inhibitors for chemical and structural similarity. Human aromatase is well known as an important pharmacological target in anti-breast cancer therapy, but recent research demonstrates its role in epileptic seizures, as well. The current antiepileptic treatment methods cause severe side effects that endanger patient health and often preclude continued use. As a result, less toxic and more tolerable antiepileptic drugs (AEDs) are needed, especially since every individual responds differently to given treatment options.MethodsThrough a pharmacophore search, this study shows that a model previously designed to search for new classes of aromatase inhibitors is able to identify antiepileptic drugs from the set of drugs approved by the Food and Drug Administration. Chemical and structural similarity analyses were performed using five potent AIs, and these studies returned a set of AEDs that the model identifies as hits.ResultsThe pharmacophore model returned 73% (19 out of 26) of the drugs used specifically to treat epilepsy and approximately 82% (51 out of 62) of the compounds with anticonvulsant properties. Therefore, this study supports the possibility of identifying AEDs with a pharmacophore model that had originally been designed to identify new classes of aromatase inhibitors. Potential candidates for anticonvulsant therapy identified in this manner are also reported. Additionally, the chemical and structural similarity between antiepileptic compounds and aromatase inhibitors is proved using similarity analyses.ConclusionsThis study demonstrates that a pharmacophore search using a model based on aromatase inhibition and the enzyme's structural features can be used to screen for new candidates for antiepileptic therapy. In fact, potent aromatase inhibitors and current antiepileptic compounds display significant - over 70% - chemical and structural similarity, and the similarity analyses performed propose a number of antiepileptic compounds with high potential for aromatase inhibition.

Anastrozole Versus Exemestane in Patients with Postmenopausal Breast Cancer and Visceral Metastases

Background: For patients with hormone receptor positive metastatic breast cancer (MBC), both steroidal and non-steroidal aromatase inhibitors (AIs) have demonstrated efficacy as initial and subsequent lines of treatment in trials comparing them with other hormonal agents like tamoxifen and megestrol acetate. Patients with MBC and predominant visceral involvement have a shortened survival compared to those with non-visceral disease. These patients are usually treated with chemotherapy, with under-utilization of endocrine strategies due to fear of rapid progression. In this review, we present the available data for both classes of AIs in patients with visceral predominant MBC and examine efficacy and safety differences between them. Methods: An exhaustive Medline search to retrieve published articles based on pre-defined inclusion criteria was conducted. Data from 13 published studies of randomized comparisons of the two classes of AIs with other hormonal therapies or each other form the basis of the efficacy analyses in this report. Conclusion: Based on our review of the available data, we argue that their manageable toxicity profile with demonstrable clinical benefit supports the use of both classes of AIs, with no significant efficacy differences between the agents, in appropriately selected patients with visceral predominant MBC. Due to the lack of randomized trial data comparing the two classes of AIs in this setting with the exception of one study, the comparisons in this review are mostly indirect and need confirmation in future prospective trials. This is likely to come from comparative trials in the adjuvant setting like the FACE and the MA-27 trials.

Clinical Evaluation of the Use of Exemestane as Further Hormonal Therapy after Nonsteroidal Aromatase Inhibitors in Postmenopausal Metastatic Breast Cancer Patients

Objectives.The aromatase inhibitors Anastrozole, Letrozole (type 2 nonsteroidal aromatase inhibitors: n-SAI) and Exemestane (type 1 steroidal aromatase inactivator) are used respectively as first- and second-line hormonal therapy in postmenopausal metastatic breast cancer women. Few clinical data are published on the sequential use of different classes of aromatase inhibitors. Methods. We report an analysis on 30 postmenopausal metastatic breast cancer women treated between January 2000 and May 2002 in 2 Italian Oncology Institutions with the hormonal sequence n-SAI (Anastrozole, Letrozole) → Exemestane. Results. When receiving n-SAI (Anastrozole 8 patients and Letrozole 22 patients), 1 out of 30 women achieved a partial response, 20 of 30 patients no change (NC) ≥6 months. The analysis of the entire population treated with Exemestane showed an overall clinical benefit (CB) of 46.6 percent (14/30) with a median duration of 12 months (95%CI 6–25) and a median time to progression (TTP) of 4 months (95%CI 1–25). Conclusions. These data confirm a partial lack of cross-resistance between n-SAI → Exemestane given in sequence.

Mechanisms of the actions of aromatase inhibitors 4-hydroxyandrostenedione, fadrozole, and aminoglutethimide on aromatase in JEG-3 cell culture

Selective inhibition of estrogen production with aromatase inhibitors has been found to be an effective strategy for breast cancer treatment. Most studies have focused on inhibitor screening and in vitro kinetic analysis of aromatase inhibition using placental microsomes. In order to determine the effects of different inhibitors on aromatase in the whole cell, we have utilized the human choriocarcinoma cell line, JEG-3 in culture to compare and study three classes of aromatase inhibitors, 4-hydroxyandrostenedione, fadrozole (CGS 16949A), and aminoglutethimide. Fadrozole is the most potent competitive inhibitor and aminoglutethimide is the least potent among the three. However, stimulation of aromatase activity was found to occur when JEG-3 cells were preincubated with aminoglutethimide. In contrast, 4-OHA and fadrozole caused sustained inhibition of aromatase activity in both JEG-3 cells and placental microsomes, which was not reversed even after the removal of the inhibitors. 4-OHA bound irreversibly to the active site of aromatase and caused inactivation of the enzyme which followed pseudo-first order kinetics. However, 4-OHA appears to be metabolized rapidly in JEG-3 cells. Sustained inhibition of aromatase induced by fadrozole occurs by a different mechanism. Although fadrozole bound tightly to aromatase at a site distinct from the steroid binding site, the inhibition of aromatase activity by fadrozole does not involve a reactive process. None of the inhibitors stimulated aromatase mRNA synthesis in JEG-3 cells during 8 h treatment. The stimulation of aromatase activity by AG appeared to be due to stabilization of aromatase protein. According to these results, 4-OHA and fadrozole would be expected to be more beneficial in the treatment of breast cancer patients than AG. The increase in aromatase activity by AG may counteract its therapeutic effect and might be partially responsible for relapse of breast cancer patients from this treatment.

Equine cytochrome P450 aromatase exhibits an estrogen 2-hydroxylase activity in vitro.

Aromatase (estrogen synthetase) is a steroidogenic enzyme complex which catalyzes the conversion of androgens to estrogens (termed aromatization). This enzyme was purified from adult equine testis to homogeneity by five chromatographic steps. The ability of purified and reconstituted equine aromatase to exhibit an estrogen 2-hydroxylase activity was tested and compared to testosterone aromatization. Enzymatic activities were assessed by tritiated water release from labelled estradiol and testosterone. Kinetic analysis of estradiol 2-hydroxylation showed an apparent K(m) of 23 microM and a V(max) of 18 nmol/min/mg, whereas the values for testosterone aromatization were a K(m) of 15.7 nM and a V(max) of 34.6 pmol/min/mg. A specific antiserum raised against purified testicular equine P450arom and known to inhibit aromatase activity [1] was also found to inhibit the estrogen hydroxylase activity of equine placental microsomes in a dose-dependent manner with an IC50 value of 15 microl serum: 0.5 ml incubate. The estrogen hydroxylase activity was inhibited in a dose-dependent manner by two classes of aromatase inhibitors, i.e. steroidal-- (4-hydroxyandrostenedione and 7alpha-([4-aminophenyl]thio)-androst-4-ene-3, 17-dione)--and non-steroidal--(fadrozole and miconazole). The IC50 values were approximately 300 and 890 nM for 4-hydroxyandrostenedione and 7alpha-([4-aminophenyl]thio)-androst-4-ene-3, 17-dione, and 92 and 285 nM, for fadrozole and miconazole, respectively. Furthermore, 4-hydroxyandrostenedione caused a time-dependent inactivation of estrogen hydroxylase activity. We conclude that equine aromatase is able to use estradiol as a substrate, and converts it to catechol estradiol in vitro, possibly using the active site of aromatization. This is the first demonstration that equine aromatase functions as an estrogen 2-hydroxylase, in addition to transforming androgens into estrogen.

Aromatase and its inhibitors in breast cancer treatment ? overview and perspective

Estrogen has an important role in stimulating the growth of breast carcinomas. Inhibition of estrogen production is therefore a logical treatment strategy. A number of selective inhibitors have been developed against aromatase, a cytochrome P-450 enzyme which catalyzes the rate limiting step in the biosynthesis of estrogens. The mechanisms of the aromatase reaction, current knowledge of the enzyme, and regulation of its expression are discussed as the basis for inhibitor development. Two classes of aromatase inhibitors, steroidal and non-steroidal compounds, are now coming into use. Among the steroid substrate analogues, 4-hydroxyandrostenedione (4-OHA) has been shown to be effective in breast cancer patients with advanced disease and was recently approved for treatment in the United Kingdom. Several different classes of compounds which act as aromatase inhibitors are currently in clinical trials and should provide breast cancer patients with a number of treatment options. Among these are highly potent and selective non-steroidal inhibitors which have recently been found to suppress plasma and urinary estrogens over 95% in breast cancer patients. The potency of these newer aromatase inhibitors provides the opportunity to determine whether complete suppression of estrogen production and action will result in enhanced tumor regression.