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The development of Casodex (bicalutamide): preclinical studies
1Cardiovascular and Musculoskeletal Research Department, Zeneca Pharmaceuticals, Macclesfield, Cheshire, UK.
European Urology
|January 1, 1996
Summary
Casodex (bicalutamide) is a potent, peripherally selective antiandrogen for prostate cancer treatment. It effectively inhibits tumor growth with improved tolerability and potency compared to flutamide.
Area of Science:
- Oncology
- Pharmacology
- Endocrinology
Background:
- Casodex (bicalutamide) was developed as a nonsteroidal antiandrogen for prostate cancer therapy.
- It is structurally related to flutamide but exhibits distinct pharmacological properties.
Purpose of the Study:
- To evaluate the preclinical antiandrogenic activity, potency, and selectivity of Casodex.
- To compare Casodex's efficacy and tolerability with flutamide in various animal models.
Main Methods:
- In vitro binding assays using androgen receptors from rat, dog, human prostate, and tumor cell lines.
- In vivo studies in rats, dogs, and monkeys to assess antiandrogenic effects and hormonal changes.
- Evaluation of tumor growth inhibition in a rat prostate cancer model.
Main Results:
- Casodex demonstrated high affinity for androgen receptors and acted as a pure antiandrogen, inhibiting androgen-stimulated gene expression and cell growth.
- In vivo studies showed Casodex to be a potent antiandrogen, particularly in dogs where it was 50 times more potent than flutamide.
- Casodex exhibited peripheral selectivity, with minimal impact on luteinizing hormone (LH) and testosterone levels, attributed to poor blood-brain barrier penetration.
Conclusions:
- Casodex possesses superior potency, tolerability, and pharmacokinetic profile for once-daily administration compared to existing antiandrogens.
- Its peripheral selectivity and efficacy in preclinical models support its use in prostate cancer treatment.