MDV3100- AN ANTI PROSTATE CANCER AGENT

by Selleckchem | Apr 09 2012

ROLE OF ANDROGEN RECEPTORS
Androgen receptors (ARs), a type of nuclear receptors that are involved in the regulation of expression of different types of genes that play role in the development and progress of male sexual characteristics. ARs can also be called as receptor subfamily number 3, C group, and member number 4 (NR3C4nuclear). Dihydrotestosterone or testosterone and androgenic hormones function as ligands for these receptors and are in turn translocated into the nucleus, where they directly or indirectly regulate the respective gene expression. Higher quantities of progestin inhibit these receptors. These receptors are known to effect many different types of genes and their expression e.g., AKT1, Cyclin D1, HDAC1, BRCA1, STAT3, SRC kinases and EGFR etc. they all are mostly cell cycle regulating proteins or oncoproteins which are malfunctioning in many different types of cancers. As they are known to affect many different types of proteins involved in signal transduction pathway they are considered responsible for many different types of cancers or according to researchers mostly they are associated or affected by ARs therefore inhibiting these receptors would be very beneficial for devising a therapy against cancer of different types.
MDV3100 androgen receptor inhibitor is one of such inhibitors. It has shown successful results in case of prostate cancers against which it has been tried. It has been developed and manufactured by Medivation, a pharmaceutical company. One can buy MDV3100 in the packing of a vial of 10 mg in around $250. MDV3100 contains a fluoromethylbenzamide group in it is soluble in DMSO. If it is stored at -20oC its stability has been ensured for up-to 2 years. MDV3100 suppliers would provide it for any purpose whether for laboratory or for research purposes.

PHARMACOLOGY OF MDV3100
Several inhibitors are there against androgenic receptors ARs. MDV3100 is a better choice as compared to e.g., anti-androgen bicalutamide compared to which it has five times higher affinity for ARs [1]. It hinders the regulation of transcription of genes involved in the progression of tumor by inhibiting nuclear translocations. Unlike bicalutamide, it checks translocation of ARs and hinders in their binding with co-activators. In contrast to bicalutamide it has also been seen to down regulate the androgen dependent TMPRSS2 (Transmembrane protease serine 2) and PSA (prostate specific antigen) genes. Bicalutamide increases their levels. If there is a W741C mutation in the cells, bicalutamide acts as an agonist of ARs and MDV3100 functions as their antagonist.

CLINICAL TRIALS AND PROSTATE CANCER PATIENTS
MDV3100 has been tried in different types of cancers especially against breast cancer but the most promising results have been found against prostate cancer. It was suggested, in phase III preclinical trial, to be very efficacious in the treatment of patients having CPRC (castration-resistant prostate cancer). The results, analyzed after a complete cycle of one month dose, showed a 90 % of decrease in the serum antigens specific to the disease. In the other studies of Phase I/II clinical trials done on metastatic surgery or castration resistant prostate cancer (mCPRC) patients, the levels of PSA have been seen to drop significantly in both treated and naive patients [2]. More clinical trials in other patients e.g., Docetaxel–immune or Docetaxel-resistant patients (NCT00974311) have been announced by the manufacturing company. Action of MDV3100 on the patients who are newly diagnosed has also been announced in Phase III clinical trials. A more important study in Phase II clinical trials is related to the observation of combined effects of MDV3100 and bicalutamide in the treated or castrated patients [3].

REFERENCES
1. Tran, C.e.a., Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science, 2005.
2. Scher, H.I.e.a., Antitumor activity of MDV3100 in a phase I/II study of castration-resistant prostate cancer (CRPC). J Clin Oncol, 2009.
3. Scher, H.I.e.a., Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. The Lancet, 2010.