Molecule

Description

Endocrinology

Description

Bicalutamide (Casodex, Cosudex, Calutide, Kalumid) is an androgen receptor (AR) antagonist with IC50 of 0.16 μM.

Targets

IC₅₀

In Vitro

Bicalutamide undergoes an antagonist-to-agonist switch, stimulating AR activity. Bicalutamide treatment of LNCaP/AR(cs) cells in absence of the synthetic androgen R1881 results in altered gene expression consistent with its well-documented agonist activity in context of AR overexpression. Bicalutamide induces cell proliferation in a dose-dependent manner, and only partially antagonized the effects of R1881. Bicalutamide treatment also results in a significant amount of nuclear AR, although less than that observed with R1881. Bicalutamide exhibits partial agonist activity as evidenced by induction of DNA binding at AR target genes and incomplete antagonism of the effects of R1881. In absence of R1881, Bicalutamide partially activates VP16-AR–mediated transcription, indicative of AR binding to DNA. In LNCaP/AR-luc cells with a stably integrates AR-driven luciferase reporter construct. In the presence of R1881, Bicalutamide shows only weak partial antagonism of VP16-AR–mediated transcription with an IC50 of 0.35 μM. ^[1] Micromolar bicalutamide causes a significant dose-dependent reduction in clonogenicity. ^[2] Dual inhibition of the AR and mTOR signaling pathways provides further benefit with the ridaforolimus-bicalutamide combination producing syner -gistic antiproliferative effects in prostate cancer cells in vitro when compared with each agent alone. ^[3]

In Vivo

Single bicalutamide reduces tumor growth by 79%, at defined submaximal doses. The ridaforolimus-bicalutamide combination exhibits improved and potent antitumor activity, almost completely abrogating tumor growth. The combination is also well tolerated, as evidenced by no significant changes in body weight over the course of treatment. Plasma PSA levels are again tightly linked to tumor growth in the combination-treated mice. ^[3]

Clinical Trials

Bicalutamide plus MDV3100 has entered in a phase II clinical trial in the treatment of prostatic neoplasms.

Features

Description

Single Bicalutamide reduces tumor growth by 79%, at defined submaximal doses. The ridaforolimus-bicalutamide combination exhibits improved and potent antitumor activity, almost completely abrogating tumor growth. The combination is also well tolerated, as evidenced by no significant changes in body weight over the course of treatment. Plasma PSA levels are again tightly linked to tumor growth in the combination-treated mice. ^[3] Bicalutamide plus MDV3100 has entered in a phase II clinical trial in the treatment of prostatic neoplasms.

Whole-cell competitive binding assays

Whole-cell competitive binding assays are performed in LNCaP/AR(codon-switch) (LNCaP/AR(cs)) (harbors a mixture of exogenous wild-type AR and endogenous mutant AR (T877A)) and cells propagated in Iscove’s or RPMI media supplemented with 10% fetal bovine serum, or during the assay with 10% charcoal-stripped, dextran-treated fetal bovine serum (CSS). Cells are pre-incubated with ¹⁸F-FDHT, increasing concentrations (1pM to 1μM) of cold Bicalutamide are added, and the assay is performed to measure specific uptake of ¹⁸F-FDHT (4). IC50 values are determined using a one site binding model with least squares curve fitting and R² > 0.99.

Cell Lines

C4-2 cell

Concentrations

0-1 μM

Incubation Time

72 hours

Methods

Exponentially growing C4-2 cells are plated into two 96-well plates and incubated overnight at 37 ?C. Twenty-four hours later one plate is aspirated and stored at -80 ?C and the other treated with 10-fold serial concentrations of ridaforolimus (1000 nM to 0.0001 nM) or vehicle (ethanol). Following 72 hours culture at 37 ?C, the plates are assessed simultaneously for cell growth using the Cy qUANT Cell Proliferation Assay kit. Bicalutamide and Ridaforolimus combination proliferation assays are performed similarly except cell growth is determined as the change in cell number between vehicle control and compound treated cells after 72 hours in culture.

Animal Models

Male nude mice bearing C4-2 cells

Formulation

4% ethanol, 5% Tween 80, and 5% propylene glycol

Doses

10 mg/kg

Administration

Administered via p.o.