This Month in Investigative Urology

Article Outline

• Viral Vector Based Prostate Cancer Vaccine Strategy
• Optimizing Nitric Oxide Production by L-Arginine in Human Corpus Cavernosum
• Enhanced Adenosine Triphosphate Release From the Urothelium of Patients With Painful Bladder Syndrome
• Erlotinib as a Potential Agent for Bladder Cancer
• Telomere Dysfunction in Peripheral Lymphocytes May be a Predisposition Factor for Renal Cancer
• Copyright

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Viral Vector Based Prostate Cancer Vaccine Strategy 

Recent studies have shown that for patients with metastatic androgen independent prostate cancer on a docetaxel based chemotherapy regimen overall survival was improved but the overall clinical benefit was an increase in survival of only around 2 months. Vaccine strategies designed to break tolerance and generate a sustained potent immune response are among the novel therapeutic approaches for the treatment of metastatic androgen independent prostate cancer currently being evaluated. Inducing T cell responses against a self-antigen can lead to antitumor activity with minimal toxicity. Prostate specific antigen (PSA) is a potential target for a prostate cancer vaccine because its expression is restricted to prostate cancer and normal prostatic epithelium. However, because PSA is a self-antigen, vaccines and vaccine strategies must be able to enhance the immunogenicity of PSA. The primary objective of this phase I study reported by Arlen et al (page 1515) from Bethesda, Maryland was to evaluate the clinical safety of a vaccine using recombinant vaccinia virus (prime) and recombinant fowlpox (rF) virus (boost) in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with prostate cancer. The vaccines contained transgenes for PSA, a triad of co-stimulatory molecules (TRICOM) and a tumor antigen whose amino acid sequence had been modified to enhance its immunogenicity. Secondary end points were immunological and clinical responses, changes in PSA velocity, and the kinetics of vaccinia virus clearance from the vaccination site, serum, peripheral blood mononuclear cells, urine and saliva. The 15 patients enrolled in this study had metastatic prostate cancer. Patients were given rF-PSA/TRICOM alone or recombinant vaccinia-PSA/TRICOM followed by rF-PSA/TRICOM on a prime and boost schedule, with or without recombinant-GM-CSF protein or rF-GM-CSF vector. Some grade 2 toxicity was seen in patients who received a higher dose of rF-GM-CSF but no toxicity exceeded grade 2. Viable vaccinia was detected after vaccination at the site swab of 1 of 4 patients analyzed. PSA specific immune responses were seen in 4 of 6 patients who were HLA-A2+ and decreases in serum PSA velocity were observed in 9 of 15 patients. Based on the safety and preliminary immunogenicity results of this trial, initiating a randomized phase II study of PSA/TRICOM vaccines in patients with less advanced prostate cancer would be possible.

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Optimizing Nitric Oxide Production by L-Arginine in Human Corpus Cavernosum 

The amino acid L-arginine contains 4 nitrogen atoms per molecule and is the precursor of nitric oxide synthesis by constitutive and inducible isoforms of nitric oxide synthase. In the penis L-arginine induced relaxation most likely occurs via nitric oxide synthase induced conversion of L-arginine to nitric oxide in the penile bulb. Gur et al (page 1543) from New Orleans, Louisiana investigated the direct relaxant effect and the time course of L-arginine substrate on the formation of nitric oxide in isolated human corpus cavernosum, determined the mechanisms underlying L-arginine induced relaxation using pharmacological methods, and evaluated the relationship between L-arginine and the cyclic guanosine monophosphate/protein kinase G pathway. Samples of human corpus cavernosum were suspended in an organ chamber for measurements of isometric tension. After precontraction with phenylephrine, concentration-response curves were performed for L-arginine. Underlying mechanisms of relaxation were evaluated by inhibitory and stimulatory agents. After a brief incubation period (1 to 4 hours) L-arginine induced minor changes in human corpus cavernosum. In contrast, when incubation time was increased (6 to 10 hours) L-arginine evoked detectable human corpus cavernosum relaxation proportional to concentration and time. Relaxation was significantly attenuated by several nitric oxide synthase inhibitors. The results demonstrated that L-arginine induces slow and prolonged relaxation of human corpus cavernosum. This may occur by restoring the endogenous amino acid pool for nitric oxide synthesis and by nitric oxide-soluble guanylyl cyclase-protein kinase G signaling involving the activation of K+ channels or by inhibiting the up-regulated RhoA/Rho-kinase pathway. The use of sildenafil combined with L-arginine further facilitates erections and may benefit men with more severe erectile dysfunction.

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Enhanced Adenosine Triphosphate Release From the Urothelium of Patients With Painful Bladder Syndrome 

Adenosine triphosphate (ATP) has been increasingly recognized as an important sensory neurotransmitter. A number of studies support the idea that mechanical stimuli can evoke the release of ATP from epithelial cells lining tubes or sacs such as the bladder. This extracellular ATP, which is most likely urothelial in origin, is implicated in distention evoked activation of bladder afferents. Once released from epithelial cells after bladder stretch, ATP is thought to activate purinergic receptors on suburothelial sensory nerves and, thus, it may have an important role in sensory functions such as nociception. Patients with a painful bladder form a heterogenous group based on a diagnosis of exclusion rather than a precise pathophysiology. Kumar et al (page 1533) from Sheffield, United Kingdom established the level of ATP release by the urothelium from painful bladders and compared it with that from the normal human bladder. Biopsies of urothelium from patients with painful bladder syndrome were subjected to stretch (by 130% and 150% of original length) and electric stimulation. There was a significantly greater release of ATP following mechanical stretch and electrical field stimulation of the urothelium from painful vs control bladders. Adenosine triphosphate may have an important role in the mechanisms governing abnormal bladder sensation. This study suggests increased purinergic activity in terms of increased ATP release in painful bladders compared to normal bladders. This could explain most symptoms resulting from this condition and it may provide a target for the development of new therapies for the various conditions that are included in this category.

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Erlotinib as a Potential Agent for Bladder Cancer 

Due to the morbidity of cytotoxic agents that currently predominate in therapeutic oncology, there has been considerable effort to generate small molecules that target specific cellular events considered important in tumor progression. Given the role of epidermal growth factor receptor (EGFR) in the promotion of cell proliferation in normal and malignant cells, it has become a target for this clinical strategy. Tyrosine kinase inhibitors are directed at the catalytic domain of the receptor where they block activation. Recent studies have shown that these EGFR inhibitors have some therapeutic efficacy in a subgroup of patients with nonsmall cell lung cancer. Tumors from these individuals harbored activating point mutations in the EGFR catalytic domain. The presence of mutations in nonsmall cell lung cancer has been determined to be the underlying determinant of the response to gefitinib and erlotinib in clinical trials. More recently similar mutations in the EGFR gene were reported in other cancers, providing the opportunity to explore additional uses of this class of inhibitor for cancer treatment. Given the putative involvement of EGFR in bladder cancer, it may be important to determine the efficacy of the small molecule EGFR inhibitors in this disease.

Jacobs et al (page 1510) from Burlington, Massachusetts evaluated the prevalence of EGFR gene mutations in bladder cancer. In addition, they examined the effects of erlotinib on bladder cancer cell proliferation, and activation of EGFR and its downstream mediators. The identification of mutations in the kinase domain of EGFR was performed using single strand conformation polymorphism. The action of erlotinib was established within a bladder carcinoma cell panel using clonogenic assays and Western blot analysis involving 112 invasive bladder tumors. Although mutations in the coding region of EGFR are rare in invasive bladder tumors, differential sensitivity to erlotinib was recorded within a panel of cell lines. Maintenance of the phosphorylation status of Akt in the presence of erlotinib along with epithelial-to-mesenchymal transition correlates with insensitivity to growth inhibition in bladder carcinoma cell lines. Even in the absence of EGFR mutations, erlotinib shows potential as a therapeutic agent for the treatment of bladder cancer.

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Telomere Dysfunction in Peripheral Lymphocytes May be a Predisposition Factor for Renal Cancer 

Telomeres, which are located at the end of chromosomes, are composed of a varying number of repetitive DNA sequences and nucleoproteins. Telomeres prevent nucleolytic degradation, end-to-end fusion and other chromosomal events that may be lethal to a cell. In human somatic cells the length of telomere repeats decreases with each cell division. After the telomeres reach a critical length cells may stop dividing and undergo apoptosis. However, some cells may bypass this signal, continue to divide and develop cancers by causing genomic instability. Telomere length in CD4 T cells, CD8 T cells and overall peripheral blood lymphocytes was measured in 65 patients with renal cell carcinoma and 65 age, sex and ethnicity matched controls by Shao et al (page 1492) from Houston, Texas. After adjustment for patient age, sex, ethnicity and smoking status, and using 75% of telomere length in controls as a cutoff, short telomere length in CD4 T cells was associated with a significantly increased risk of renal cell carcinoma. Similar trends were observed in CD8 T cells and overall peripheral blood lymphocytes. The data strongly support the hypothesis that telomere shortening in peripheral blood lymphocytes is a genetic predisposing factor for cancer.