Effects of Dutasteride on Prostate Growth in the Large Probasin-Large T Antigen Mouse Model of Prostate Cancer

Shao, Tsang C.; Li, H.; Ittmann, Michael; Cunningham, Glenn R.

doi:10.1016/j.juro.2007.05.118

Cited by 8 publications

(9 citation statements)

References 19 publications

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“…Dutasteride has been shown to kill prostate cancer cells both in vitro [3,4] and in vivo [5,6]. In previous studies we determined changes in gene expression profiles in a number of prostate cancer cell lines following dutasteride treatment in vitro [4,7].…”

Section: Introductionmentioning

confidence: 99%

Effects of the 5 alpha‐reductase inhibitor dutasteride on gene expression in prostate cancer xenografts

et al. 2009

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Background In the prostate, androgens play a crucial role in normal and cancerous growth; hence the androgenic pathway has become a target of therapeutic intervention. Dutasteride is a 5 alpha-reductase (5AR) inhibitor currently being evaluated both for chemoprevention and treatment of prostate cancer. Dutasteride inhibits both 5AR I and II enzymes, effectively blocking conversion of testosterone to dihydrotestosterone (DHT) in the prostate. This greatly reduces the amount of the active ligand DHT available for binding to the androgen receptor (AR) and stimulating proliferation, making this a good candidate for chemoprevention of prostate cancer. In this study, we sought to determine how dutasteride is functioning at the molecular level, using a prostate cancer xenograft model. Methods Androgen-responsive LuCaP 35 xenograft tumors were grown in Balb/c mice. Subcutaneously implanted time-release pellets were used for drug delivery. Microarray analysis was performed using the Affymetrix HG-U133Av2 platform to examine changes in gene expression in tumors following dutasteride treatment. Results Dutasteride significantly reduced tumor growth in LuCaP 35 xenografts by affecting genes involved in apoptotic, cytoskeletal remodeling, and cell cycle pathways among others. Notably, genes in the Rho GTPase signaling pathway, shown to be important in androgen-deprivation conditions, were significantly up-regulated. Conclusion We have identified multiple pathways outside of the androgenic pathway in prostate cancer xenografts affected by treatment with dutasteride. These findings provide insights into the function of dutasteride within the tumor microenvironment, potentially allowing for development of agents that can be used in combination with this drug to further enhance its effectiveness.

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Section: Introductionmentioning

confidence: 99%

Effects of the 5 alpha‐reductase inhibitor dutasteride on gene expression in prostate cancer xenografts

et al. 2009

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“…This is also not consistent with increased apoptosis in human prostate cancer following androgen withdrawal [41], LPB-Tag mice dorsolateral [42] and human prostate following dutasteride treatment [35], and castrated C57BL/6 TRAMP mice prostate [36]. Previous studies found that finasteride shrunk prostate volume and caused epithelial involution through induction of apoptosis to inhibit tumor growth [43, 44].…”

Section: Discussionmentioning

confidence: 94%

The impact of finasteride and dutasteride treatments on proliferation, apoptosis, androgen receptor, 5α-reductase 1 and 5α-reductase 2 in TRAMP mouse prostates

Opoku-Acheampong

Henningson

Lindshield

2017

Heliyon

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BackgroundPreviously, we studied the effect of finasteride- or dutasteride-containing diets in male C57BL/6 TRAMP x FVB mice. Pre (6 weeks of age) and post (12 weeks of age) groups received finasteride or dutasteride to determine the efficacy of these pharmaceuticals on prostate cancer (PCa) development in male C57BL/6 TRAMP x FVB mice. Post-Dutasteride treatment was more effective than Pre-Dutasteride treatment, and dutasteride treatments were more effective than finasteride treatments in decreasing prostatic intraepithelial neoplasia (PIN) progression and PCa development. Finasteride and Pre-Dutasteride treatments significantly decreased high-grade PIN incidence, but increased poorly differentiated PCa incidence. In this study, molecular changes in prostates of these mice were characterized in an effort to elucidate the discordant response in Pre-Dutasteride and finasteride groups, and determine why Post-Dutasteride treatment was more effective.Method/Principal findingsKi-67 (proliferation marker) and androgen receptor (AR) protein, apoptotic DNA fragmentation (TUNEL assay), 5α-reductase 1 (5αR1) and 5α-reductase 2 (5αR2) mRNA were quantified in male TRAMP mice prostate tissues with genitourinary weight < 1 and > 1 gram. Overall, proliferation and AR were decreased and apoptosis was increased in most tumors versus prostate epithelium and hyperplasia. Proliferation and AR were increased notably in hyperplasia versus prostate epithelium and tumor. There were no clear trends or differences in 5α-reductase 1 and 5α-reductase 2 levels between large and small tumors. The discordant response in Pre-Finasteride and Pre-Dutasteride groups may be due to upregulated 5αR1 levels in large versus small tumors. It is not clear what the mechanism is for the different response in the Post-Finasteride group. Post-Dutasteride treatment was more effective than Pre-Dutasteride treatment in decreasing 5αR1 in large tumors. Therefore, this may be why this treatment was more effective in decreasing PIN progression and PCa development.ConclusionThe effect of finasteride and dutasteride on these biomarkers did not clearly elucidate their mechanism of action, but tumor 5αR1 levels were significantly positively correlated with adjusted prostate severe lesion score.

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“…Another study that used the same scoring system also found fewer statistical differences in the ventral lobe in response to tomato powder and soy germ diets, especially compared with the dorsal and lateral lobes [28]. This decrease in efficacy in the ventral lobe might be explained by the fact that in large probasin-large T antigen mice, dutasteride markedly decreased the dorsolateral prostate weights but had little to no effect on ventral prostate weights [29]. In addition, rat ventral prostate has almost two-fold higher concentrations of testosterone and dihydrotestosterone than the dorsolateral prostate; furthermore, after finasteride administration, ventral prostate lobe concentrations of testosterone are almost twice as high as dorsolateral prostate lobe concentrations [30].…”

Section: Discussionmentioning

confidence: 99%

“…However, dutasteride has decreased body weight or body weight gain in other studies. For example, dutasteride administration at doses of 2.5 and 5 mg/kg body weight to 8-week-old male Sprague–Dawley rats for 2 weeks led to a significant decrease in their body weights [32], and 4 or 8 weeks of infusion of 2 mg/kg body weight dutasteride treatment led to a significant decrease in body weight gain in large probasin-large T antigen transgenic mice [29]. In our study, the mice were consuming ~8 mg/kg finasteride and dutasteride/day.…”

Section: Discussionmentioning

confidence: 99%

Preventive and Therapeutic Efficacy of Finasteride and Dutasteride in TRAMP Mice

et al. 2013

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BackgroundThe prostate cancer prevention trial (PCPT) and Reduction by dutasteride of Prostate Cancer Events (REDUCE) trial found that 5α-reductase (5αR) inhibitors finasteride and dutasteride respectively, decreased prostate cancer prevalence but also increased the incidence of high-grade tumors. 5αR2 is the main isoenzyme in normal prostate tissue; however, most prostate tumors have high 5αR1 and low 5αR2 expression. Because finasteride inhibits only 5αR2, we hypothesized that it would not be as efficacious in preventing prostate cancer development and/or progression in C57BL/6 TRAMP x FVB mice as dutasteride, which inhibits both 5αR1 and 5αR2.Method/Principal FindingsSix-week-old C57BL/6 TRAMP x FVB male mice were randomized to AIN93G control or pre- and post- finasteride and dutasteride diet (83.3 mg drug/kg diet) groups (n =30–33) that began at 6 and 12 weeks of age, respectively, and were terminated at 20 weeks of age. The pre- and post- finasteride and dutasteride groups were designed to test the preventive and therapeutic efficacy of the drugs, respectively. Final body weights, genitourinary tract weights, and genitourinary tract weights as percentage of body weights were significantly decreased in the Pre- and Post-dutasteride groups compared with the control. The Post-dutasteride group showed the greatest inhibition of prostatic intraepithelial neoplasia progression and prostate cancer development. Surprisingly, the Post-dutasteride group showed improved outcomes compared with the Pre-dutasteride group, which had increased incidence of high-grade carcinoma as the most common and most severe lesions in a majority of prostate lobes. Consistent with our hypothesis, we found little benefit from the finasteride diets, and they increased the incidence of high-grade carcinoma.ConclusionOur findings have commonalities with previously reported PCPT, REDUCE, and the Reduction by dutasteride of Clinical Progression Events in Expectant Management (REDEEM) trial results. Our results may support the therapeutic use of dutasteride, but not finasteride, for therapeutic or preventive use.

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Effects of Dutasteride on Prostate Growth in the Large Probasin-Large T Antigen Mouse Model of Prostate Cancer

Cited by 8 publications

References 19 publications

Effects of the 5 alpha‐reductase inhibitor dutasteride on gene expression in prostate cancer xenografts

Effects of the 5 alpha‐reductase inhibitor dutasteride on gene expression in prostate cancer xenografts

The impact of finasteride and dutasteride treatments on proliferation, apoptosis, androgen receptor, 5α-reductase 1 and 5α-reductase 2 in TRAMP mouse prostates

Preventive and Therapeutic Efficacy of Finasteride and Dutasteride in TRAMP Mice

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