This Month in Investigative Urology

Article Outline

• Should Conventional Chemotherapy for Kidney Cancer be Reevaluated?
• Renal Ischemic Preconditioning Improves Recovery of Kidney Function
• Vascular Targeted Photodynamic Therapy in Renal Tissue
• Calcium Signaling and Mechanical Activity in the Human Ureter
• Notch-1 and Jagged-1 Expression in Bladder Cancer is Related to Survival
• Copyright

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Should Conventional Chemotherapy for Kidney Cancer be Reevaluated? 

Kidney cancer is notoriously difficult to treat when metastatic due to its resistance to conventional chemotherapy. Thus, the 5-year survival rate of patients with metastatic renal cell carcinoma is less than 10% and novel approaches to treatment are needed. The cyclin kinase inhibitor p21 generally conveys an anti-apoptotic function through its induction by the DNA damage responsive p53 pathway. Park et al (page 352) from Davis, California capitalized on this function of p21 and used an antisense approach to sensitize p53-wt renal cell carcinoma cells to chemotherapy induced apoptosis by attenuating p21 protein levels. The human renal cell carcinoma cell lines ACHN and SN12C were transfected with antisense and control oligodeoxynucleotides, and assessment of p21 and apoptosis relevant protein levels as well as apoptosis were performed using standard techniques. Pre-incubation of the renal cancer cells with phosphorothioate antisense p21 oligodeoxynucleotide markedly attenuated p21 and sensitized cells to the apoptosis induced by doxorubicin and cisplatin, such that an order of magnitude less of doxorubicin or cisplatin could be used in the presence of antisense to achieve equivalent or greater cell death. Since phosphorothioate antisense oligodeoxynucleotides accumulate to a higher degree in the kidney and liver than in any other organ, these findings suggest a reevaluation of conventional chemotherapy in kidney cancer in association with antisense p21 oligodeoxynucleotide.

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Renal Ischemic Preconditioning Improves Recovery of Kidney Function 

Ischemia preconditioning, a phenomenon induced by brief ischemia and reperfusion periods, renders an organ more tolerant to subsequent ischemia/reperfusion injury. The mechanisms of ischemic preconditioning remain unclear, although since its initial description the mechanisms of action have been studied, elucidated and reviewed. Ischemic preconditioning would have useful applications in the fields of organ transplantation and nephron sparing surgery. Timsit et al (page 388) from Lyon, France determined the role of ischemic preconditioning in renal function and histology in a rat model. Rats were divided into 6 groups including sham operation, ischemic preconditioning alone, ischemia alone, ischemic preconditioning before bilateral ischemia, ischemic preconditioning before ischemia in left nephrectomized rats and ischemic preconditioning of the left kidney alone before 60 minutes of bilateral warm ischemia to assess the effect of left kidney preconditioning on the contralateral kidney. The study showed that ischemic preconditioning improves the ability of rat kidneys to tolerate subsequent ischemic injury in the first 3 days after reperfusion. Moreover, fibrosis and α-smooth muscle actin expression are decreased in ischemic preconditioning kidneys 15 days after reperfusion, suggesting a potential interest of ischemic preconditioning in surgical situations that expose kidneys to prolonged warm ischemia.

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Vascular Targeted Photodynamic Therapy in Renal Tissue 

Photodynamic therapy is a unique form of therapy by which a photochemical reaction generates free radicals with the capability of causing tissue injury and necrosis. A new generation of photodynamic therapy is now available with unique properties that are advantageous in comparison to those of traditional photodynamic therapy. These properties include rapid clearance resulting in minimal phototoxicity and sequestration in the vascular compartment, which may have some advantages from a selectivity and toxicity perspective. Unique targeting by the new generation of photodynamic therapy agents has motivated this application to be called vascular targeted photodynamic therapy (VTP). Based on this recent availability of VTP, Matin et al (page 338) from Houston, Texas performed a pilot trial evaluating its safety and efficacy for treating renal tissue. All kidneys in surviving animals functioned on nuclear renography. Renal function remained unchanged. Histology showed a distinct demarcation between the treated zone and the surrounding parenchyma at higher doses. Significant tissue effect with some necrosis was seen at low drug/light combinations. This study provides the initial proof of principle that justifies further preclinical investigation of VTP for renal tumors.

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Calcium Signaling and Mechanical Activity in the Human Ureter 

Floyd et al (page 398) from Liverpool, United Kingdom determined the mechanisms of calcium signaling in the human ureter, and the relationship to peristaltic contractions and bundular structure in living tissue. Confocal imaging of 31 ureters, and simultaneous force and calcium measurements were made, along with immunohistochemistry and Western blotting. Fast propagating Ca waves spread throughout the bundles, and were closely associated with contraction and depended on L-type Ca channel entry. Modulation of Ca and K channel activity was a potent mechanism for affecting Ca and force, whereas manipulation of the sarcoplasmic reticulum had little effect. These first measurements of Ca signals in the human ureter obtained during phasic contractions and in response to agonists show that it is controlled by fast propagating Ca waves, which spread rapidly between the muscle bundles producing regular contractions. Drugs that interfere with excitability or Ca entry through L-type Ca channels have profound effects on Ca signaling and contractility.

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Notch-1 and Jagged-1 Expression in Bladder Cancer is Related to Survival 

Notch signaling participates in embryonic development by maintaining the self-renewal potential of some tissues, and it can positively or negatively influence proliferation, differentiation and apoptosis depending on the cell type. To date 4 Notch receptors have been identified (Notch 1 to 4) in humans with corresponding ligands including Delta-like-1, 3 and 4, and Jagged-1 and 2. Some tissue systems show that aberrant Notch signaling promotes tumorigenesis. However, there is increasing evidence that Notch signaling is not exclusively oncogenic, and that it can instead function as a tumor suppressor. To date the Notch pathway has rarely been associated with bladder transitional cell carcinoma. In a study by Shi et al (page 361) from the Hubei Province, China, the expression of Notch ligands and receptors was detected in normal and tumorous human bladder transitional epithelium. The expression of Notch-1 to 3, Jagged-1 and Delta-like-1 was detected in 70 cases of bladder carcinoma, 10 of normal urothelium and 2 cell lines (T24 and BIU-87), respectively. The 5 kinds of Notch factors were intensively stained in normal bladder transitional epithelium immunohistochemically but expression was significantly decreased in tumor tissues. Moreover, expression of the 5 genes in papillary tumors was lower than in invasive tumors, but only Notch-1 and Jagged-1 showed a statistically significant difference. Postoperative disease-free survival of patients with low Notch-1 and Jagged-1 expression was significantly shorter than that of patients with other expression patterns in papillary tumors. The Notch family expression pattern in papillary transitional cell carcinoma of the bladder is different from that of invasive bladder transitional cell carcinoma. Low expression of Notch-1 and Jagged-1 is potentially a useful marker for the survival of patients with papillary bladder transitional cell carcinoma.