New study below.
"One mechanism that provides CaP resistance to ADT is primary backdoor androgen metabolism, which uses up to four 3α-oxidoreductases to convert 5α-androstane-3α,17β-diol (DIOL) to dihydrotestosterone (DHT)."
In other words, a possible pathway to CRPC involves the generation of DHT other than from testosterone [T]. i.e. other than from 5alpha-reductase [5AR] conversion of T to DHT.
Dutasteride (Avodart) is a 5AR inhibitor [5ARI]. In the U.S., the FDA has approved Dutasteride for the treatment of benign prostatic hyperplasia (BPH). Avodart is not generally used against PCa, because castration therapy is assumed to remove enough T, that DHT cannot possibly be a problem. & so, doctors might measure T while men are on ADT, but ignore DHT.
Yet, as Dr. Myers has said - T is not the problem, DHT drives PCa. Myers would prescribe Avodart for men with castrate T but non-castrate DHT. Sometimes, one cap per week was enough to control DHT.
IMO, it is prudent to use Avodart while on ADT. I use it as prophylactic, rather than corrective.
Myers tested DHT, but does serum DHT reflect DHT levels in CRPC cells? Why would it?
Avodart might perhaps prolong the effectiveness of ADT for some (although you can't block all of the CRPC escape pathways.)
Is a 5ARI sufficient?
"... combined treatment using catalytically inactive 3α-oxidoreductase mutants and the 5α-reductase inhibitor, dutasteride, decreased DHT levels in CaP cells better than dutasteride alone. Combined blockade of frontdoor and backdoor pathways of DHT synthesis provides a therapeutic strategy to inhibit CRPC development and growth."
Dr. Myers seems to have been able to get serum DHT to castrate levels with Avodart alone, in backdoor DHT producers, so I'm not inclined to be overly concerned about the new findings.
-Patrick
ncbi.nlm.nih.gov/pubmed/295...
Oncotarget. 2018 Jan 10;9(13):11227-11242. doi: 10.18632/oncotarget.24107. eCollection 2018 Feb 16.
Inhibition of dihydrotestosterone synthesis in prostate cancer by combined frontdoor and backdoor pathway blockade.
Fiandalo MV1, Stocking JJ1, Pop EA1, Wilton JH1,2, Mantione KM2, Li Y1, Attwood KM3, Azabdaftari G4, Wu Y1, Watt DS5, Wilson EM6, Mohler JL1.
Author information
1
Department of Urology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
2
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
3
Department of Biostatistics and Bioinformatics Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
4
Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
5
Center for Pharmaceutical Research and Innovation and Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA.
6
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
Abstract
Androgen deprivation therapy (ADT) is palliative and prostate cancer (CaP) recurs as lethal castration-recurrent/resistant CaP (CRPC). One mechanism that provides CaP resistance to ADT is primary backdoor androgen metabolism, which uses up to four 3α-oxidoreductases to convert 5α-androstane-3α,17β-diol (DIOL) to dihydrotestosterone (DHT). The goal was to determine whether inhibition of 3α-oxidoreductase activity decreased conversion of DIOL to DHT. Protein sequence analysis showed that the four 3α-oxidoreductases have identical catalytic amino acid residues. Mass spectrometry data showed combined treatment using catalytically inactive 3α-oxidoreductase mutants and the 5α-reductase inhibitor, dutasteride, decreased DHT levels in CaP cells better than dutasteride alone. Combined blockade of frontdoor and backdoor pathways of DHT synthesis provides a therapeutic strategy to inhibit CRPC development and growth.
KEYWORDS:
3α-oxidoreductases; androgen deprivation therapy; androstanediol; dihydrotestosterone; dutasteride
PMID: 29541409 PMCID: PMC5834294 DOI: 10.18632/oncotarget.24107
Avodart / Dutasteroid
