PNU 157706, a novel dual type I and II5α-reductase inhibitor

Salle, E. Di; Giudici, D.; Radice, A.; Zaccheo, T.; Ornati, G.; Nesi, Marcella; Panzeri, A.; Délos, Sylvie; Martin, Pièrre‐Marie

doi:10.1016/s0960-0760(97)00158-1

Cited by 41 publications

(24 citation statements)

References 37 publications

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“…This finding is consistent with the fact that all of these drugs are competitive inhibitors of 5a-reductase (Stoner, 1996;di Salle et al, 1998;Frye et al, 1998). All of the somatic SRD5A2 missense substitutions analysed significantly modified the apparent K i of the normal protein for all three steroid 5a-reductase inhibitors examined (Table 4).…”

Section: Discussionsupporting

confidence: 84%

Identification and characterization of somatic steroid 5α-reductase (SRD5A2) mutations in human prostate cancer tissue

2004

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Prostate cancer is a very common disease in industrialized countries and it is known to be androgen-dependent. The human SRD5A2 gene encodes the prostatic (or type II) steroid 5a-reductase, which catalyses the irreversible conversion of testosterone to dihydrotestosterone (DHT), the most active androgen in the prostate. We have sequenced the entire protein-coding region of this locus in 30 microdissected prostate adenocarcinomas. We identified a total of 17 de novo amino-acid substitutions in 13 of these tumors. We also identified six additional silent substitutions. In total, 18 out of 30 (60%) of the tumors examined had de novo somatic substitutions in the prostatic steroid 5a-reductase-coding region. We also characterized all of the SRD5A2 missense substitutions biochemically and pharmacologically, using three 5a-reductase inhibitors, including finasteride. The biochemical parameters of the distinct 5a-reductase missense substitutions varied substantially. We note that two out of the three recurrent SRD5A2 missense substitutions increased 5a-reductase in vitro activity, while the third one is essentially neutral. These findings are consistent with a role for increased DHT levels in the prostate through increased activity of the SRD5A2 locus in prostate cancer progression, in a subset of patients. Our pharmacologic studies also reveal substantial variability for each 5a-reductase inhibitor. These data, therefore, should be taken into account in both prevention as well as therapeutic trials of prostate cancer utilizing 5a-reductase inhibitors.

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Section: Discussionsupporting

confidence: 84%

Identification and characterization of somatic steroid 5α-reductase (SRD5A2) mutations in human prostate cancer tissue

2004

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“…Thus, hydrophobic interactions between the 4-azasteroid (finasteride/dutasteride) and specific wild-type 5 -reductase residues may be important for the slow, time-dependent inhibition displayed by these inhibitors. Pharmacogenetic analysis of these 5 -reductase variants with another 4-azasteroid, such as PNU157706 (di Salle et al 1998) may be instrumental in confirming this observation.…”

Section: Discussionmentioning

confidence: 79%

Pharmacogenetic analysis of human steroid 5α reductase type II: comparison of finasteride and dutasteride

Makridakis

Reichardt

2005

Journal of Molecular Endocrinology

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Human steroid 5 -reductase type II is a prostate-specific, membrane-associated enzyme that catalyzes the conversion of testosterone to dihydrotestosterone, the most potent androgen in the prostate gland. Genetic variants of this enzyme have been associated with both the development and the progression of prostate cancer. Both finasteride and dutasteride are competitive inhibitors of the type II steroid 5 -reductase that have been effectively used for the treatment of benign prostatic hyperplasia. Finasteride has also been successfully utilized for prostate cancer chemoprevention. We here investigate 5 -reductase inhibition assays in vitro to measure the effect of incubation time on the apparent inhibition constant (K i ) for both constitutional and somatic (prostate cancer) enzyme variants. Our systematic pharmacogenetic analysis shows that both finasteride and dutasteride are slow, time-dependent inhibitors of steroid 5 -reductase type II, and that the inhibition kinetics depend on the 5 -reductase genotype. We also show that, overall, dutasteride is a more efficient steroid 5 -reductase inhibitor than finasteride. Based on our data, we are able to map areas of the enzyme that are responsible for this time-dependent inhibition for either (or both) enzyme inhibitor(s). This comprehensive pharmacogenetic analysis of steroid 5 -reductase variants unveiled significant pharmacogenetic variation for both finasteride and dutasteride and thus should be taken into account when designing protocols for treatment and/or chemoprevention of prostatic diseases with either one of these 5 -reductase inhibitors since there is considerable pharmacogenetic variation for both drugs.

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“…The roles of the genes under investigation are illustrated in Figure 1 and include: CYP17 (cytochrome P-450 steroid 17a-hydroxylase/17,20 lyase), a gene that encodes an enzyme involved in testosterone synthesis within the testes; 9 SRD5A2 (steroid 5a reductase type II), a gene that encodes for the enzyme which converts testosterone to dihydrotestosterone (DHT), its more active metabolite within the prostate; 10,11 the AR (androgen receptor), which binds testosterone and DHT and upregulates prostate cell growth; 12 and the VDR (vitamin D receptor), which binds vitamin D and downregulates prostate growth. 13 Two AR gene polymorphisms have been extensively investigated with regard to CaP risk and include a polyglutamine (CAG) repeat and a polyglycine (GGC) repeat, both of which are found in the first exon encoding the N-terminal modulatory domain of the AR (the domain that binds to androgen response elements to regulate gene expression).…”

Section: Introductionmentioning

confidence: 99%

Association between hormonal genetic polymorphisms and early-onset prostate cancer

Forrest

Edwards

Houlston

et al. 2005

Prostate Cancer Prostatic Dis

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We investigated the association between seven polymorphisms in four candidate genes involved in vitamin D and androgen metabolism with early-onset prostate cancer (CaP) risk. The polymorphisms were genotyped in 288 UK males who were diagnosed with CaP at the age of 55 y or younger and up to 700 population-based controls. An additional 50 cases (not selected for age) and 76 controls were also genotyped. Short (p22 repeats) AR (CAG) n repeats were associated with a significantly reduced risk of early onset CaP (OR 0.68, 95% CI 0.50-0.91) compared with men with long (422) repeats. Men homozygous for the leucine variant of SRD5A2 p.89V4L were also found to be at a significantly increased risk of CaP compared with men who were homozygous for the valine allele (OR 1.84, 95% CI 1.15-2.98). No associations were found with the AR (GGC) n , CYP17 Msp A1 I, VDR Taq I, SRD5A2 (TA) n and p.49A4T polymorphisms and CaP risk. These findings suggest that common polymorphisms in the AR and SRD5A2 genes may be associated with early-onset CaP in British men.

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PNU 157706, a novel dual type I and II5α-reductase inhibitor

Cited by 41 publications

References 37 publications

Identification and characterization of somatic steroid 5α-reductase (SRD5A2) mutations in human prostate cancer tissue

Identification and characterization of somatic steroid 5α-reductase (SRD5A2) mutations in human prostate cancer tissue

Pharmacogenetic analysis of human steroid 5α reductase type II: comparison of finasteride and dutasteride

Association between hormonal genetic polymorphisms and early-onset prostate cancer

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