Aldo-Keto Reductase 1C3 Inhibitor Prodrug Improves Pharmacokinetic Profile and Demonstrates In Vivo Efficacy in a Prostate Cancer Xenograft Model.

Aldo-keto reductase 1C3 (AKR1C3) is overexpressed in castration-resistant prostate cancer where it acts to drive proliferation and aggressiveness by producing androgens. The reductive action of the enzyme leads to chemoresistance development against various clinical antineoplastics across a range of cancers. Herein, we report the continued optimization of selective AKR1C3 inhibitors and the identification of 5r, a potent AKR1C3 inhibitor (IC50 = 51 nM) with >1216-fold selectivity for AKR1C3 over closely related isoforms. Due to the cognizance of the poor pharmacokinetics associated with free carboxylic acids, a methyl ester prodrug strategy was pursued. The prodrug 4r was converted to free acid 5r in vitro in mouse plasma and in vivo. The in vivo pharmacokinetic evaluation revealed an increase in systemic exposure and increased the maximum 5r concentration compared to direct administration of the free acid. The prodrug 4r demonstrated a dose-dependent effect to reduce the tumor volume of 22Rv1 prostate cancer xenografts without observed toxicity.

[The effect of trilostane and dexamethasone on serum amino acids and TNF in endotoxemic rats].

By the use of specific endogenous GC biosynthesis inhibitor Trilostane and exogenous GC Dexamethasone (Dex), we established three rat models with similar severity of endotoxemia, but different plasma GC level. With these models we studied the effect of elevated plasma GC on serum TNF, pathological changes of vital organs and the changes in serum amino acids and glucose concentration in comparable endotoxemic condition. It was observed that plasma GC level was negatively correlated with the maximum TNF concentration, but positively correlated with the liver tyrosine transaminase activity, serum amino acids and glucose concentrations and as the serum GC level was elevated, the pathological changes of intestine, stomach, liver and lungs became less pronounced. From these results, it was supposed that in severe endotoxemia hypersecration of endogenous GC and maintenance of high level plasma GC are essential for animals to alleviate tissue injuries by reducing the overproduction of the host-derived mediators such as TNF and promoting the metabolism of amino acids and glucose.

[Effect of cholesterol oxidase on the involution of experimental hypercholesterolemia in rabbits]. / Vliianie kholesterinoksidazy na obratnoi razvitie eksperimental'noi giperkholesterinemii u krolikov.

Cholesterol oxidase (3 beta-hydrosteroid oxidase), isolated from Actinomyces lavendulae, oxidized unesterified cholesterol in rabbit blood serum without detergents in vitro. Intravenous administration of the enzyme into hypercholesterolemic rabbits at a dose of 0.5-2.0 un/kg decrease distinctly the cholesterol content in blood. The rate of the decrease depended on the dose of the preparation. Acute toxicity of the cholesterol oxidase preparations for mice correlated with the degree of purification of the enzyme. Cholesterol oxidase from Act. lavendulae may be considered as a potential hypocholesterolemic drug.