Combination Antiangiogenic and Androgen Deprivation Therapy for Prostate Cancer

Nicholson, Brandi T.; Gulding, Kathryn M; Conaway, Mark; Wedge, Stephen R.; Theodorescu, Dan

doi:10.1158/1078-0432.ccr-04-0902

Cited by 27 publications

(22 citation statements)

References 21 publications

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“…Thus, targeting the event of angiogenesis by specific antiangiogenic compounds for antitumor effects requires identification of an optimal stage of tumor growth for therapeutic intervention. Many of the preclinical animal studies validating antiangiogenic drugs, recombinant factors, and gene transfer approaches have been done in immunodeficient animals (23)(24)(25)(26). Despite promising results, in these models, the kinetics of implanted tumor growth and the relevance of cell lines studied to the pattern of primary growth and spontaneous progression of human tumor are highly limited.…”

Section: Discussionmentioning

confidence: 99%

“…The accuracy of tumor grade at these time points was determined to be >80%. For treatment studies, 22 mice were included for sacrifice at each time point (12,18,24,28, and 32 weeks; 110 mice in total) for pathologic evaluation, and 14 mice were included for end point survival. There were three time points for treatment with rAAV-GFP and rAAV-(E+A) namely 5, 10, and 18 weeks of age.…”

Section: Methodsmentioning

confidence: 99%

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Effects of Sustained Antiangiogenic Therapy in Multistage Prostate Cancer in TRAMP Model

et al. 2007

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Antiangiogenic therapy is a promising alternative for prostate cancer growth and metastasis and holds great promise as an adjuvant therapy. The present study evaluated the potential of stable expression of angiostatin and endostatin before the onset of neoplasia and during the early and late stages of prostate cancer progression in transgenic adenocarcinoma of mouse prostate (TRAMP) mice. Groups of 5-, 10-, and 18-weekold male TRAMP mice received recombinant adeno-associated virus-6 encoding mouse endostatin plus angiostatin (E+A) by i.m. injection. The effects of therapy were determined by sacrificing groups of treated mice at defined stages of tumor progression and following cohorts of similarly treated mice for long-term survival. Results indicated remarkable survival after recombinant adeno-associated virus-(E+A) therapy only when the treatment was given at an earlier time, before the onset of high-grade neoplasia, compared with treatment given for invasive cancer. Interestingly, early-stage antiangiogenic therapy arrested the progression of moderately differentiated carcinoma to poorly differentiated state and distant metastasis.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Effects of Sustained Antiangiogenic Therapy in Multistage Prostate Cancer in TRAMP Model

et al. 2007

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“…This suggests that prostate blood vessels are dependent on signaling through VEGFR2, and also likely EGFR, present on prostate blood vessels (11,21,25). These effects were anticipated as previous studies have shown that this compound slows growth of s.c. transplanted human prostate cancer cell lines, such as the PC3 and LnCaP, principally by inhibiting angiogenesis (31)(32)(33). Direct effect mediated by the VEGFR2 and EGFR present on the AT-1 cells (and possibly also RET kinase; ref.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to our findings in the orthotopic model, ZD6474 was more effective than castration in inhibiting growth of s.c. transplanted, androgen-sensitive human LnCaP cells (32). This discrepancy is, however, anticipated as the castration response in s.c. LnCaP tumors may be suboptimal as such tumors are not supported by an androgen-regulated stroma and vasculature.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of Castration in an Orthotopic Model of Androgen-Independent Prostate Cancer Can Be Mimicked and Enhanced by Angiogenesis Inhibition

Hammarsten¹,

Halin²,

Wikstöm³

et al. 2006

Clinical Cancer Research

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Purpose: Today, the most important treatment of advanced prostate cancer is castration; unfortunately, however, the long-term effect of this therapy is insufficient. Recent studies suggest that castration-induced prostate involution could be caused by primary effects in the prostate vasculature; therefore, we examined if antivascular treatments could mimic the effects of castration. Experimental Design: Androgen-independent AT-1prostate cancer cells were grown inside the ventral prostate in adult rats. Tumor-bearing animals were treated with an inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor signaling, N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine (ZD6474, AstraZeneca, So« derta« lje, Sweden), and short-term effects (after 3 days) were compared with those induced by castration. Results: Castration caused decreased vascular density in the normal tissue surrounding the tumor and consequently increased tumor hypoxia and apoptosis, and moderately decreased tumor growth. ZD6474 treatment resulted in decreased tumor vascular density accompanied by increased tumor hypoxia, apoptosis, and decreased tumor growth, suggesting that castration and antiangiogenic therapy work through similar mechanisms. Interestingly, castration or ZD6474 alone worked by reducing vascular density in the surrounding normal tissue and ZD6474 also in the tumor. Combined treatment with castration + ZD6474 was more effective than castration and ZD6474 alone in inducing tumor hypoxia, apoptosis, necrosis, and decreasing tumor vascular density. Conclusion: These findings show that a drug that targets the vasculature in the tumor and in the surrounding ventral prostate lobe could mimic and even enhance the effects of castration. Our present findings thus suggest that castration + ZD6474 could be a particularly effective way to treat prostate tumors.

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“…Surgical castration in mice bearing LNCaP tumors arrests tumor growth (11). However, this antitumor effect of androgen ablation is temporary.…”

Section: Discussionmentioning

confidence: 99%

Docetaxel Followed by Castration Improves Outcomes in LNCaP Prostate Cancer–Bearing Severe Combined Immunodeficient Mice

Tang¹,

Khan²,

Goloubeva

et al. 2006

Clinical Cancer Research

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Purpose: Androgen ablation is the standard initial treatment for advanced prostate cancer; however, tumors eventually develop androgen independence and become incurable. Chemotherapy is commonly used after hormone treatment fails but has not shown significant survival benefit. Studies suggest that androgen ablation can select for a population of hormoneindependent cells that are also relatively chemotherapy resistant. Thus, it may be therapeutically advantageous to target prostate cancer with chemotherapy before hormone ablation. This study was undertaken to determine the relative efficacy of such an approach in a preclinical model of prostate cancer. Experimental Design: Severe combined immunodeficient mice bearing human LNCaP prostate tumors were treated with docetaxel and/or surgical castration applied singly, concurrently, or in different sequences.Treatment efficacy was determined by tumor volume and growth delay measurements. The extent of apoptosis in tumors in response to treatments was assessed via terminal deoxynucleotidyl transferase^mediated nick-end labeling (TUNEL) assays. In addition, Western blots were done to study the relative expression of Bcl-2 and Bax in the tumors. Results: Docetaxel followed by castration showed the most potent antitumor effects. In contrast, with the exception of castration alone, castration followed by docetaxel produced the least antitumor activity.TUNEL assays confirmed that the density of apoptotic tumor cells was significantly greater for docetaxel followed by castration than for any other treatment. In tumors of mice treated with single modality therapies, Bax to Bcl-2 ratios decreased significantly after castration, whereas this ratio remained high after docetaxel treatment. Conclusion: A treatment sequence of docetaxel followed by hormone ablation may be more effective in treating prostate cancer than concurrent docetaxel/hormone therapy or hormone ablation followed by docetaxel.

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Combination Antiangiogenic and Androgen Deprivation Therapy for Prostate Cancer

Cited by 27 publications

References 21 publications

Effects of Sustained Antiangiogenic Therapy in Multistage Prostate Cancer in TRAMP Model

Effects of Sustained Antiangiogenic Therapy in Multistage Prostate Cancer in TRAMP Model

Inhibitory Effects of Castration in an Orthotopic Model of Androgen-Independent Prostate Cancer Can Be Mimicked and Enhanced by Angiogenesis Inhibition

Docetaxel Followed by Castration Improves Outcomes in LNCaP Prostate Cancer–Bearing Severe Combined Immunodeficient Mice

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