Anastrozole

Synthetic Routes: Anastrozole is synthesized through a multistep process. The key step involves the coupling of 1,2,4-triazole with a phenylmethyl group, followed by nitrile addition. The overall reaction sequence leads to the formation of the compound.

Industrial Production: this compound is produced industrially using efficient synthetic routes.

Reactivity: Anastrozole undergoes various chemical reactions due to its structural features. These include oxidation, reduction, and substitution reactions.

Common Reagents and Conditions: Specific reagents and conditions depend on the desired transformation. For example

Major Products: The products formed from these reactions include modified derivatives of this compound, which may have altered pharmacological properties.

Treatment of Breast Cancer

Anastrozole is indicated for:

• Adjuvant Therapy : Used as an adjunct treatment for early-stage hormone receptor-positive breast cancer in postmenopausal women.
• First-Line Treatment : Recommended for hormone receptor-positive or unknown locally advanced or metastatic breast cancer in postmenopausal women.
• Second-Line Treatment : Effective for advanced breast cancer in patients who have progressed after tamoxifen therapy.

Clinical Efficacy : this compound has shown comparable efficacy to tamoxifen and megestrol acetate in various studies. For instance, a phase III trial demonstrated that this compound significantly increased survival time compared to megestrol acetate (median time to death: 26.7 months vs. 22.5 months) .

Breast Cancer Prevention

This compound has been evaluated for its preventive effects in high-risk populations:

• IBIS-II Trial : In a randomized trial involving 3,864 postmenopausal women at high risk for breast cancer, this compound reduced the incidence of breast cancer by 49% compared to placebo over a median follow-up of 131 months .

Pharmacokinetics and Dosage

This compound is administered orally, with a typical dosage of 1 mg per day being effective for most indications. It achieves maximal suppression of estrogen levels at dosages greater than or equal to 1 mg/day .

Side Effects and Tolerability

The most common side effects associated with this compound include:

• Gastrointestinal disturbances (29-33%)
• Headaches (≤18%)
• Hot flushes (≤12%)
• Bone pain (≤12%)

Overall, this compound is generally well-tolerated compared to other treatments like megestrol acetate, which is often associated with weight gain .

Emerging Applications

Recent studies have explored additional applications of this compound beyond oncology:

• Antiviral Properties : Research indicates that this compound may exhibit antiviral activity against human coronaviruses by reducing inflammation and inhibiting specific inflammatory pathways . This suggests potential off-label uses that warrant further investigation.

Estrogen Suppression: Anastrozole inhibits the enzyme aromatase, which converts androgens to estrogens. By blocking this process, it reduces estrogen levels in the body.

Molecular Targets: Aromatase itself is the primary molecular target. By inhibiting it, this compound disrupts estrogen synthesis.

Pathways Involved: The compound impacts estrogen-dependent pathways, influencing cell growth and proliferation in hormone receptor-positive breast cancer cells.

Anastrozole vs. Letrozole

Letrozole, another nonsteroidal AI, exhibits greater in vitro aromatase inhibition potency than this compound. For example:

• In advanced breast cancer, letrozole and this compound showed comparable overall response rates (ORR: 15% in both) and median overall survival (OS: 30.5 vs. 33.3 months) .

This compound vs. Exemestane

Exemestane, a steroidal AI, irreversibly inhibits aromatase. Clinical comparisons show:

• Similar ORR (15% vs. 15%) and OS (30.5 vs. 33.3 months) in advanced breast cancer .
• Exemestane may have a marginally better toxicity profile regarding musculoskeletal adverse events, though data are inconclusive .

This compound vs. Fulvestrant

Fulvestrant, a selective estrogen receptor downregulator (SERD), is often combined with this compound. In the SWOG S0226 trial:

• Combination Therapy : Fulvestrant + this compound improved median OS to 49.8 months vs. 42.0 months for this compound alone (HR: 0.82; P=0.03), particularly in patients without prior tamoxifen exposure (OS: 52.2 vs. 40.3 months) .

Combination Therapies and Synergistic Agents

This compound + mTOR Inhibitors

In the VICTORIA trial for endometrial cancer, adding vistusertib (mTOR inhibitor) to this compound increased the 8-week progression-free rate to 67.3% vs. 39.1% with this compound alone, demonstrating enhanced efficacy without significant toxicity escalation .

This compound + Vitamin D Analogs

Preclinical studies show that vitamin D compounds PRI-2191 and PRI-2205 enhance this compound activity:

• Tumor growth inhibition (TGI) reached 60.1% (vs. 30% for this compound alone) in breast cancer models .

This compound + EGFR Inhibitors

In tamoxifen-resistant ER+ metastatic breast cancer, this compound + gefitinib improved progression-free survival (14.7 vs. 8.4 months) and clinical benefit rates (49% vs. 34%) compared to this compound alone .

Pharmacodynamic and Pharmacokinetic Variability

Inter-Individual Variation

• Plasma this compound concentrations vary widely, with 4% of patients showing paradoxical rises in estrogen levels due to extensive phase II enzyme-mediated conjugation .
• Genetic polymorphisms (e.g., rs11648166 in SLC38A7) influence plasma drug levels, highlighting the need for personalized dosing .

Estrogen Suppression Efficacy

• Letrozole suppresses plasma estradiol below detection limits in 92% of patients vs. 42% with this compound, yet clinical outcomes remain comparable .

Data Tables

Table 1. Clinical Outcomes of this compound vs. Other AIs

Table 2. This compound Combination Therapies

Anastrozole, a selective aromatase inhibitor, is primarily used in the treatment of hormone receptor-positive breast cancer in postmenopausal women. Its mechanism of action involves inhibiting the aromatase enzyme, which is responsible for converting androgens into estrogens. This reduction in estrogen levels is crucial since many breast cancers are stimulated by estrogen. This article delves into the biological activity of this compound, highlighting its effects on estrogen levels, bone metabolism, and clinical efficacy based on various studies.

This compound works by competitively inhibiting aromatase, leading to a significant decrease in circulating estrogens. The primary sites of action include:

• Adrenal Glands : Where most estrogens are synthesized post-menopause.
• Peripheral Tissues : Such as adipose tissue and the liver.

The inhibition results in a reduction of serum estradiol levels by approximately 70% within 24 hours of administration, with sustained suppression for up to six days after discontinuation of therapy .

Effects on Estrogen Levels

A study involving 34 postmenopausal women with advanced breast cancer demonstrated significant reductions in serum estrogen levels after 2 weeks of this compound treatment:

These findings indicate that this compound effectively suppresses estrogen synthesis, which is critical for its role in treating hormone-sensitive breast cancers .

Impact on Bone Metabolism

This compound has been associated with changes in bone metabolism markers. Research indicates that while it significantly reduces estrogen levels, it may also affect bone density:

• Bone Resorption Markers : Increased levels of C-terminal telopeptide of type I collagen (ICTP) and N-telopeptide (NTx) were observed.
• Bone Formation Markers : A significant increase in bone alkaline phosphatase (BAP) and osteocalcin (BGP) was noted over time.

In patients with bone metastases, the increase in resorption markers was statistically significant, suggesting a potential risk for osteoporosis or fractures during long-term therapy .

Clinical Efficacy

This compound's efficacy has been demonstrated across various studies:

• Breast Cancer Prevention Trial :
  • In a randomized trial involving 4,000 postmenopausal women at high risk for breast cancer, those taking this compound showed a significant reduction in breast cancer incidence compared to the placebo group.
  • Results after five years indicated only 35 cases of breast cancer among those treated with this compound versus 89 cases in the placebo group .
• First-Line Therapy for Advanced Breast Cancer :
  • This compound was shown to be superior to tamoxifen in terms of overall response rates and tolerability when used as first-line therapy for advanced breast cancer .
  • The study reported a clinical benefit rate and longer progression-free survival compared to traditional therapies.
• Rare Cohorts Study :
  • In patients with recurrent uterine leiomyosarcomas and carcinosarcomas, this compound demonstrated a clinical benefit rate of 35% at three months, indicating its potential utility beyond breast cancer treatment .

Safety Profile

While this compound is generally well-tolerated, it does carry risks such as:

• Increased incidence of ischemic cardiovascular events.
• Decreased bone mineral density, necessitating monitoring during long-term use .

Basic Research Questions

Q. What molecular mechanisms underpin anastrozole’s efficacy in hormone receptor-positive breast cancer, and how do these inform preclinical model selection?

this compound selectively inhibits aromatase, reducing estrogen synthesis. Preclinical models should prioritize estrogen-dependent tumor xenografts in ovariectomized animals to mimic postmenopausal physiology. In vitro assays must measure aromatase activity in adipose or stromal cells, as tumor cells often lack aromatase expression .

Q. What are the standard endpoints and biomarkers used in Phase III trials evaluating this compound as adjuvant therapy?

Primary endpoints include disease-free survival (DFS) and time to progression (TTP). Biomarkers: ER/PR status (IHC), Ki-67 proliferation index, and circulating estrogen levels. Secondary endpoints: overall survival (OS) and safety profiles (e.g., bone density loss, cardiovascular events) .

Q. How do pharmacokinetic properties of this compound influence dosing regimens in diverse patient populations?

this compound’s bioavailability (83%) and half-life (~50 hours) support once-daily dosing. Population pharmacokinetic studies should account for hepatic CYP3A4 metabolism, particularly in patients with polymorphisms affecting enzyme activity. No dose adjustment is needed for renal impairment .

Advanced Research Questions

Q. How can researchers address contradictory efficacy outcomes in cross-trial comparisons of this compound and exemestane?

Discrepancies (e.g., TTP in Japanese vs. global cohorts) may arise from genetic variability in CYP19A1 or differences in trial design (e.g., blinding, radiographic review protocols). Meta-analyses using individual patient data (IPD) and sensitivity analyses for ethnicity-specific subgroups are recommended .

Q. What statistical methods are optimal for analyzing heterogeneous treatment effects in this compound trials with long-term follow-up?

Use Cox proportional hazards models with time-varying covariates to adjust for evolving risk factors (e.g., osteoporosis). Frailty models or machine learning (e.g., random survival forests) can identify subgroups with divergent responses to prolonged therapy .

Q. How should researchers design studies to evaluate this compound’s role in chemoprevention, balancing efficacy and toxicity?

Adaptive trial designs (e.g., Bayesian response-adaptive randomization) allow dynamic allocation to this compound or placebo based on interim safety/efficacy data. Primary endpoints: incidence of ER+ ductal carcinoma in situ (DCIS); secondary: fracture rates, lipid profiles .

Q. What methodologies resolve contradictions in biomarker data (e.g., Ki-67 suppression vs. survival benefit) in this compound studies?

Integrate multi-omics approaches (transcriptomics, proteomics) to identify compensatory pathways (e.g., HER2 upregulation). Pathologic complete response (pCR) may not correlate with survival in ER+ tumors; instead, focus on residual cancer burden (RCB) indexes .

Q. Methodological Guidance Tables

Table 1: Key Considerations for this compound Trial Design

Table 2: Common Pitfalls in this compound Research