PSA Decline Is an Independent Prognostic Marker in Hormonally Treated Prostate Cancer

Palmberg, Christian; Koivisto, Pasi A.; Visakorpi, Tapio; Tammela, Teuvo L.J.

doi:10.1159/000067996

Cited by 64 publications

(40 citation statements)

References 24 publications

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“…Although disputed, CAB therapy seems to provide slight improvement in 5-year survival over AWT (Prostate Cancer Trialists' Collaborative Group, 2000), and it has become an approved treatment for advanced CaP. Up to 90% of CaPs initially respond to hormonal therapy (Palmberg et al, 1999), but eventually, they acquire a therapy-resistant phenotype, resulting in disease recurrence after a few months or years.…”

mentioning

confidence: 99%

Androgen Receptor Alterations in Prostate Cancer Relapsed during a Combined Androgen Blockade by Orchiectomy and Bicalutamide

Haapala

Hyytinen

Roiha

et al. 2001

Laboratory Investigation

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SUMMARY:Mechanisms of prostate cancer (CaP) recurrence during a combined androgen blockade (CAB) are poorly understood. Previously, the role of androgen receptor (AR) gene mutations underlying the CAB therapy relapse has been raised. To investigate the hypothesis that AR gene aberrations are involved in CAB relapse, 11 locally recurrent CaP samples from patients treated with orchiectomy and bicalutamide were analyzed for copy number changes and DNA sequence alterations of the AR gene by fluorescence in situ hybridization and single-strand conformation polymorphism, respectively. Altogether, base changes were detected in four tumors (36%). Three of them were missense mutations (G166S, W741C, M749I) and two were silent polymorphisms. Interestingly, none of the tumors had AR amplification. These data suggest that different AR variants are developed and selected for during various types of hormonal treatments, and also, that CAB achieved by orchiectomy and bicalutamide does not act as a selective force for AR amplification. (Lab Invest 2001, 81:1647-1651.

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mentioning

confidence: 99%

Androgen Receptor Alterations in Prostate Cancer Relapsed during a Combined Androgen Blockade by Orchiectomy and Bicalutamide

Haapala

Hyytinen

Roiha

et al. 2001

Laboratory Investigation

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“…Serum prostate-specific antigen levels are key indicators of response to therapy in prostate cancer (26), and this is true for both localized and metastatic disease. In addition, in patients treated with androgen deprivation, prostate-specific antigen levels may initially drop more abruptly than the decrease in tumor burden.…”

Section: Zd6474 Is Superior To Orchiectomy In Maintainingmentioning

confidence: 99%

“…In addition, in patients treated with androgen deprivation, prostate-specific antigen levels may initially drop more abruptly than the decrease in tumor burden. This is because prostate-specific antigen is an androgen-regulated gene (26). However, prostate-specific antigen expression is also influenced by non-androgen-dependent mechanisms (27).…”

Section: Zd6474 Is Superior To Orchiectomy In Maintainingmentioning

confidence: 99%

Combination Antiangiogenic and Androgen Deprivation Therapy for Prostate Cancer

Nicholson¹,

Gulding²,

Conaway³

et al. 2004

Clinical Cancer Research

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Purpose: Androgen ablation therapy leads to mild regression or stabilization of prostate cancer, followed by progression to the fatal androgen-independent state. Whereas androgen ablation diminishes tumor angiogenesis by suppressing vascular endothelial growth factor (VEGF) production, androgen-independent disease is marked by androgen-independent VEGF expression. We examined combined androgen ablation and inhibition of VEGF signaling in an androgen-sensitive human prostate cancer xenograft model (LNCaP) that is known to develop androgenindependent growth after androgen ablation.Experimental Design: N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine (ZD6474) is an orally active inhibitor of VEGF receptor tyrosine kinase activity, with additional activity against epidermal growth factor receptor tyrosine kinase. ZD6474 (50 mg/kg/d, per os) was administered to groups of castrated and noncastrated athymic mice bearing established (4 -616 mm 3 ) LNCaP xenografts. To evaluate the extent of tumor regrowth after ZD6474, treatment was stopped after 40 days of continuous dosing, and subsequent tumor growth was monitored. Prostate-specific antigen expression was assessed to determine the effect of ZD6474 on androgen-regulated genes.Results: In comparison with orchiectomy, ZD6474 treatment produced greater tumor growth inhibition (P < 0.001), inducing complete cytostasis for the duration of dosing. An analysis of serum prostate-specific antigen concentration and tumor weight indicated that ZD6474 did not have a direct effect on androgen-related gene expression. Combination therapy (castration plus ZD6474) produced a comparable therapeutic effect to treatment with ZD6474 alone (in noncastrated mice), for the duration of ZD6474 administration. However, when ZD6474 treatment was discontinued, the rate of tumor regrowth was significantly less in the combination group. Tumors from mice receiving combined treatment were also found to be more necrotic than tumors from mice receiving either androgen ablation or ZD6474 alone.Conclusions: These data indicate that inhibition of VEGF signaling produces a highly significant inhibition of tumor growth in a human androgen-dependent prostate tumor model, which far exceeds that produced by androgen ablation alone. However, when ZD6474 treatment is removed, concurrent androgen ablation produces a greater inhibition of tumor regrowth than is observed in mice without androgen ablation. Increased necrosis observed in tumors from orchiectomized mice receiving ZD6474 also suggests benefit from combining anti-androgen and anti-VEGF signaling approaches.

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“…The expression of PSA, an AR target gene, has been used as the most useful diagnostic marker to monitor progression of prostate cancer (27,28). As depicted in Fig.…”

Section: Dara55 Reduces the Agonist Activity Of Antiandrogens In Prosmentioning

confidence: 99%

Inactivation of androgen receptor coregulator ARA55 inhibits androgen receptor activity and agonist effect of antiandrogens in prostate cancer cells

Rahman

Miyamoto

Lardy

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Antiandrogens given to antagonize androgen receptor (AR) activity gradually lose their efficacy as antagonists and eventually function as agonists to promote (instead of block) AR-mediated growth of prostate cancer cells. The mechanisms of how antiandrogens acquire this agonist activity during hormonal therapy are largely unknown. Here, we report that expression of a dominant-negative AR-associated protein 55 (dARA55) coregulator, inhibits AR transcriptional activity and reduces the agonist activity of antiandrogens. Inducibly expressed dARA55 inhibits prostate-specific antigen and cell growth in prostate cancer cells. Further dissection of the molecular mechanism shows dARA55 can selectively suppress endogenous AR-associated protein 55 (ARA55) enhanced AR transactivation by means of interruption of dimerization between ARA55 and ARA55. These results were confirmed by using RNA interference-mediated silencing of the ARA55 gene. These results therefore provide evidence that AR function could be suppressed without mutation or change in AR itself. Taken together, these findings not only demonstrate the important roles of the ARA55 coregulator in the AR-mediated growth of prostate cancer, they also may provide a critical target for developing therapeutic agents for the antiandrogen therapy that almost always fails in the treatment of hormone-refractory prostate cancer.

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PSA Decline Is an Independent Prognostic Marker in Hormonally Treated Prostate Cancer

Cited by 64 publications

References 24 publications

Androgen Receptor Alterations in Prostate Cancer Relapsed during a Combined Androgen Blockade by Orchiectomy and Bicalutamide

Androgen Receptor Alterations in Prostate Cancer Relapsed during a Combined Androgen Blockade by Orchiectomy and Bicalutamide

Combination Antiangiogenic and Androgen Deprivation Therapy for Prostate Cancer

Inactivation of androgen receptor coregulator ARA55 inhibits androgen receptor activity and agonist effect of antiandrogens in prostate cancer cells

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