Novel Metabolically Stable PCA-1/ALKBH3 Inhibitor Has Potent Antiproliferative Effects on DU145 Cells In Vivo.

Novel potent prostate cancer antigen-1 (PCA-1)/alpha-ketoglutarate-dependent dioxygenase alkB homolog 3 (ALKBH3) inhibitors both in vivo and in vivo were designed and evaluated by a stability assay in an S9 mixture, a mixture of rat liver homogenate and co-factors, and oral absorbability assay in rat, as well as enzyme and cell assays, and resulted in the synthesis of a novel potent PCA-1/ALKBH3 inhibitor in vivo. Among them, compound 7l exhibited potent inhibitory activities in a xenograft model bearing DU145 tumor at 10 mg/kg by subcutaneous administration without negative side-effects. This inhibitory activity in vivo was more potent than that of HUHS015 at 32 mg/kg, a known PCA-1/ALKBH3 inhibitor, or docetaxel at 2.5 mg/kg, the drug clinically used for androgen-independent prostate cancer.

Systematic Trial for Evaluating Docetaxel in a Human Prostate Cancer Cell DU145 Xenograft Model.

The inhibitory activities of docetaxel at a wide range of doses (0.1-10 mg/kg; subcutaneously (s.c.), once/week) in nude mice bearing a human prostate cancer cell (DU145), xenograft model with implantation of DU145 cells or a DU145 solid tumor were examined. This systematic trial demonstrated that (i) docetaxel was more effective in the xenograft model formed by implantation of DU145 cells than in the solid DU145 tumor; (ii) administration of 2.5 mg/kg docetaxel was the critical dose because inhibitory activities were not observed at 2.5 mg/kg, while they were noted at 5 mg/kg and 10 mg/kg in both implantation approaches; (iii) edema-like effects (plump body shape and legs) were observed in both groups at 2.5 mg/kg and the tumor sizes, often increased by blood plasma and other fluids, as well as body weights were higher than at other doses; and (iv) suppression of body weight gain was observed at 10 mg/kg docetaxel.