This Month in Investigative Urology

Article Outline

• Proteomic Identification Predicts Interleukin-2 Therapy Response in Renal Cancer
• Anti-Angiogenic Gene Therapy for Renal Cancer
• Selective Prostate Cancer Ablation With Laser Activated Gold Nanoshells
• TIMP3 Promoter Methylation is a Prognostic Factor for Bladder Cancer
• Tadalafil Prevents Apoptotic Cell Death in the Penis Following Denervation
• Copyright

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Proteomic Identification Predicts Interleukin-2 Therapy Response in Renal Cancer 

Aggressive treatment with radical nephrectomy and immunotherapy has been shown to provide a survival benefit in patients with metastatic renal cell carcinoma (RCC), and retrospective data suggest that 5-year survival rates were improved when interleukin (IL)-2 was used as adjunctive immunotherapy. Although IL-2 administration offers the possibility of a durable complete response, it is associated with considerable toxicity, while only a small subset of patients responds to therapy. There is no reliable single marker available to identify patients who are more likely to respond to IL-2 therapy. Mass spectrometry based technologies such as surface enhanced laser desorption/ionization time-of-flight (SELDI-TOF) have become the methods of choice in biomarker discovery, and enable the separation of proteins and peptides according to their mass-to-charge ratio. To detect a predictive protein profile that distinguishes between IL-2 therapy responders and nonresponders among patients with metastatic RCC, Jones et al (page 730) from Boston, Massachusetts used SELDI-TOF mass spectrometry. Protein extracts from 56 patients with metastatic clear cell RCC obtained from radical nephrectomy specimens and before IL-2 therapy were applied to protein chip arrays of different chromatographic properties and analyzed. From a total of 513 protein peaks a predictor set of 11 peaks was found that performed optimally in predicting IL-2 response status. The ability to predict the probability of IL-2 response could permit targeted selection of the patients most likely to respond to IL-2 while avoiding unwanted toxicity in those less likely to respond. This proteomic predictor has the potential to aid clinicians in the deciding on appropriate therapy for patients with metastatic RCC.

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Anti-Angiogenic Gene Therapy for Renal Cancer 

Antiangiogenic therapy holds promise as an inhibitor of tumor neovasculature and a potential agent for metastatic RCC. A number of endogenous molecules have antiangiogenic properties as well, such as endostatin, angiostatin and Tie2. Mellon et al (page 737) from Indianapolis, Indiana investigated the antiangiogenic and antitumor properties of 2 adenoviral vectors expressing an endostatin-angiostatin fusion protein (Ad-EndoAngio) and a soluble, endothelium specific tyrosine kinase receptor (Ad-Tie2) in a mouse RCC xenograft model. Bilateral subcutaneous RCC tumors were induced in athymic nude mice. On days 2 and 10 following tumor establishment the mice were intratumorally injected with an adenoviral vector in the right flank only. Tumor volume was measured biweekly for 60 days. Tumors treated with Ad-EndoAngio, Ad-green fluorescent protein plus Ad-EndoAngio and Ad-EndoAngio plus Ad-Tie2 demonstrated 82%, 83% and 87% growth reduction, respectively, compared to controls. In vivo imaging showed a reduction in blood vessel number, lumen diameter and flow velocity in all 3 treatment groups. Adenoviral vectors expressing endostatin-angiostatin fusion protein have effective antiangiogenic action against human RCC cells and potential as a treatment for metastatic renal cell carcinoma.

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Selective Prostate Cancer Ablation With Laser Activated Gold Nanoshells 

Technologies such as radio frequency ablation, cryotherapy and high intensity focused ultrasound are challenged by the delicate balance among accurate tumor targeting, energy delivery and preservation of surrounding vital structures. Recent advances in nanotechnology may lead to clinically useful alternatives that are smaller, more precise and easily manipulated. Laser activated gold nanoshell thermal ablation represents a contemporary, emerging, minimally invasive technology that may offer precise thermal ablation of cancer. Gold nanoshells can be designed to absorb near infrared light, thereby converting light energy to heat sufficient to achieve selective thermal ablation. Stern et al (page 748) from Dallas, Texas evaluated the efficacy of this technology in eradicating prostate cancer in a subcutaneous tumor model in mice using a prostate cancer cell line (PC3). Animals received either a low or high dose of nanoshells via tail vein injection. Control animals received saline. A near infrared laser was aimed at the tumor bed for 3 minutes. There was 93% tumor necrosis and regression in the high dose treated group. The ablation zone was sharply limited to the laser spot size. There was no difference in the size or tumor histology of the control groups, indicating a benign course for near infrared laser treatment alone. Laser activated gold nanoshell ablation is an effective and selective technique for prostate cancer ablation in an ectopic murine tumor model.

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TIMP3 Promoter Methylation is a Prognostic Factor for Bladder Cancer 

Tissue inhibitor of metalloproteinases-3 (TIMP-3) is 1 of 4 members of a family of proteins originally classified according to their ability to inhibit matrix metalloproteinases. Hoque et al (page 743) from Baltimore, Maryland analyzed TIMP-3 methylation in 175 urine sediment DNA samples from patients with bladder cancer with well characterized clinicopathological parameters. Urine sediment DNA was examined for aberrant methylation of 9 genes including TIMP-3 by quantitative fluorogenic real-time polymerase chain reaction. The risk of death was statistically significantly higher in patients with higher TIMP-3 and ARF methylation. TIMP-3 methylation was an independent prognostic factor for bladder cancer survival with stage and metastasis. These results suggest that TIMP-3 promoter methylation could be a clinically applicable marker for bladder cancer progression. Testing for relevant epigenetic markers in voided urine holds promise for detection and more individualized therapeutic strategies. Restoring the function of TIMP-3, when lost, might be a useful intervention for gene therapy for bladder cancer, including treatment with demethylating agents.

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Tadalafil Prevents Apoptotic Cell Death in the Penis Following Denervation 

Despite techniques to preserve the cavernous nerves during radical prostatectomy erectile dysfunction remains a complication. Lysiak et al (page 779) from Charlottesville, Virginia determined whether bilateral cavernous nerve resection induces apoptosis in the penis, whether treatment with the phosphodiesterase-5 inhibitor tadalafil prevents apoptosis as well as the specific mechanisms involved. Mice were subjected to cavernous nerve resection or sham surgery, and penises were processed for the identification of apoptotic cells, changes in phosphorylation of several protein kinases and immunolocalization of specific kinases. Mice were also placed on tadalafil or vehicle after cavernous nerve resection and the penises were analyzed. An increase in apoptotic cavernous smooth muscle and endothelial cells was evident by 2 weeks, which further increased at 4 and 6 weeks after cavernous nerve resection. Apoptosis coincided with an increase in phosphorylation of c-jun N-terminal kinase and p38 mitogen activated protein kinase. Treatment with tadalafil decreased the number of apoptotic cells, and increased the phosphorylation of the 2 survival associated kinases Akt and extracellular signal-regulated kinase ½. These results provide a rationale for the early use of phosphodiesterase-5 inhibition following radical prostatectomy or extensive pelvic surgery, during which there may be injury to the cavernous nerves, to aid in the return of erectile function.