This Month in Investigative Urology

Article Outline

• Clinical Significance of Chromogranin A and Endothelin-1 in Prostate Cancer
• TRAIL Plus IFNα Induces Renal Cell Carcinoma Apoptosis
• S(MeO)TLC is Potent Chemotherapy for Bladder Cancer
• Autologous Vein Graft and Endoluminal Stent for Ureteral Defect Lesion Reconstruction
• Copyright

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Clinical Significance of Chromogranin A and Endothelin-1 in Prostate Cancer 

Chromogranin A (CHGA) has been used as a candidate marker for diagnosis and prediction of the prognosis of prostate cancer. Endothelins (ETs) exert paracrine and autocrine effects through cell-surface receptors, and are known to influence cellular processes such as angiogenesis, cellular proliferation, tissue repair and development. Ma et al (page 1182) from Japan investigated the clinical significance of CHGA polymorphism, and CHGA and ET-1 expression in prostate cancer.

Men with the GG genotype of the Glu264Asp polymorphism of CHGA had a 2.05 times higher risk of prostate cancer than men with the CC genotype (p = 0.014). In prostate cancer samples a higher CHGA immunohistochemistry grade was associated with higher stage and Gleason score (p = 0.011 and 0.044, respectively). Multivariate analysis showed that CHGA immunohistochemistry grade was an independent variable for predicting biochemical failure after radical prostatectomy (p = 0.023). Increased ET-1 expression was observed in prostate cancer lesions (p = 0.011), especially those with a higher Gleason score (p = 0.042). There was no significant relationship among the CHGA polymorphisms, and CHGA and ET-1 expression. The authors conclude that CHGA polymorphism, and CHGA and ET-1 expression have clinical significance in prostate cancer. In addition, CHGA expression was an independent predictor of biochemical failure after prostatectomy for localized prostate cancer.

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TRAIL Plus IFNα Induces Renal Cell Carcinoma Apoptosis 

Metastatic renal cell carcinoma (RCC) is resistant to traditional cytotoxic chemotherapy, and is treated with various forms of immunotherapy and targeted therapies. Immunotherapy, including interferon (IFN)-α and interleukin-2, induces a response in 10% to 20% of cases, only a third of which are durable complete responses. Targeted therapies, such as small molecule tyrosine kinase inhibitors, monoclonal antibodies to vascular endothelial growth factor and inhibitors of mammalian target of rapamycin, have improved the outlook for advanced RCC but cure remains rare and novel forms of therapy are being actively investigated. Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a novel anti-neoplastic agent in early phase clinical trials.

Clark et al (page 1166) from Nashville, Tennessee treated RCC cell lines with recombinant TRAIL and/or IFNα. TRAIL and IFNα synergistically increased apoptotic cell death in RCC cells. IFNα altered the ability of the cells to activate ERK. Inhibiting ERK with UO126 abrogated the apoptotic synergy between TRAIL and IFNα. IFNα did not induce changes in TRAIL or death receptor expression, nor did it change other known mediators of the intrinsic and extrinsic apoptotic cascade in RCC cells. The authors conclude that TRAIL plus IFNα synergistically induces apoptosis in RCC cells and that the mechanism is due at least in part to IFNα mediated changes in extracellular signal-regulated kinase activation. They further suggest that combination therapy with TRAIL and IFNα may be a novel approach to systemically treat advanced RCC and that this approach warrants further testing in vivo.

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S(MeO)TLC is Potent Chemotherapy for Bladder Cancer 

Invasive bladder cancer accounts for 25% of all bladder cancers. It has a poor prognosis with 5-year survival rates of 10% to 50%. The combination of methotrexate, vinblastine, doxorubicin and cisplatin can be used for advanced cases with systemic spreading of disease but the response rate is only 46% to 60% and novel therapeutic approaches are required. The mitotic kinesin Eg5 has a crucial role in the formation and maintenance of the bipolar spindle during mitosis and has been identified as an attractive target for cancer therapies. Ding et al (page 1175) from Japan examined the anticancer activity of a novel Eg5 inhibitor for bladder cancer, particularly metastatic disease. They examined bladder cancer cell lines and clinical tissue samples for Eg5 expression, and analyzed the antiproliferative activity of 5 Eg5 inhibitors.

Eg5 expression was increased in bladder cancer samples compared to that in normal bladder epithelium. Of the 5 Eg5 inhibitors S(MeO)TLC exhibited the strongest antiproliferative activity and induced cell death after mitotic arrest via the caspase dependent apoptotic pathway. S(MeO)TLC effectively suppressed tumor growth in vivo in subcutaneous and metastatic xenograft models. Survival times of S(MeO)TLC treated nude mice were significantly longer than those of untreated mice (p <0.001). The authors conclude that S(MeO)TLC has considerable anticancer activity, is an effective treatment for bladder cancer metastasis in a mouse model and, thus, has clinical potential.

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Autologous Vein Graft and Endoluminal Stent for Ureteral Defect Lesion Reconstruction 

Iatrogenic lesions of the ureter are common after laparoscopic gynecological procedures and invasive endourological interventions, and require elaborate surgical interventions such as autotransplantation or ureter replacement using small bowel. Studies have shown that reconstruction of bile duct defect lesions is possible with a venous interponate that has been temporarily stented. Wolters et al (page 1197) from Germany developed a technique for ureteral defect reconstruction in a pig model using an autologous vein graft splinted by an endoluminal biodegradable polylactate acid stent. In 42 pigs the external jugular vein was removed and used as an autologous vein graft. After median laparotomy a 3 cm segment was resected from the proximal ureter and replaced by the vein with or without endoluminal biodegradable polylactate acid stent.

After 6 months the stent material had completely broken down and the vein graft had been relined with urothelium, resembling the native ureter with Ck7 positive columnar epithelium and newly formed capillaries in the ureteral wall. All animals showed normal kidney function without congestion of the renal pelvis. The authors conclude that this new technique for ureteral defect is feasible and constitutes an interesting clinical alternative due to the preservation of physiological urine passage and antireflux mechanism.