Biomedical subjects
Publications and source records attributed to Christian Doehn.
We present a rare case of mesonephroid adenocarcinoma arising from mesonephroid metaplasia of the urinary bladder. For the first time, the unique histopathologic features in this patient provide evidence for the theory that vesical mesonephroid adenocarcinoma might be a highly aggressive metaplastic variant of urothelial carcinoma that should be treated accordingly.
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In total, 70-80% of newly diagnosed bladder cancers are confined to the mucosa and staged as Ta, T1 or carcinoma in situ according to the 2002 tumor, lymph nodes and metastasis classification. The standard treatment for these nonmuscle-invasive bladder cancers is transurethral tumor resection with or without adjuvant intravesical chemotherapy or intravesical immunotherapy and subsequent follow-up. Diagnosis and follow-up of nonmuscle-invasive bladder cancer offers two main problems. First, approximately 10-20% of all tumors are not seen in standard cystoscopy. Additionally, frequently repeated follow-up cystoscopies are bothersome for the patient. As an adjunct to standard cystoscopy, fluorescence-guided cystoscopy has demonstrated significantly higher tumor detection rates and optimized patient treatment in recent Phase III studies. Second, routinely performed urine cytology is characterized by high specificity but low sensitivity. Today, several urine tests are available that may increase diagnostic accuracy and potentially prolong intervals of follow-up cystocopy. Owing to rather high recurrence rates after transurethral tumor resection in most tumors and high progression rates in poorly differentiated tumors, adjuvant intravesical chemotherapy or intravesical immunotherapy has gained widespread use in patients with nonmuscle-invasive bladder cancer. Only a few further immunomodulatory drugs, such as recombinant cytokines, have shown significant clinical effectiveness. Additional approaches, such as photodynamic therapy with different photosensitizers and thermotherapy in combination with intravesical chemotherapy, have been evaluated in Phase III studies.
Ferring Research Ltd and licensee Astellas Pharma Inc are developing the gonadotropin-releasing hormone antagonist degarelix as a potential subcutaneous treatment for prostate cancer.
OBJECTIVE: To evaluate the effects of suppressing the expression of Ki-67 (expressed in proliferating cells) by antisense oligonucleotides (asON) directed against Ki-67 (which specifically inhibit the proliferation of tumour cells and tumour growth in cell culture and in subcutaneous murine tumour models) on the growth, cell viability and angiogenic activity of a preclinical renal cell carcinoma (RCC) severe combined immunodeficiency disease (SCID) mouse model. MATERIALS AND METHODS: Human RCC cells (SK-RC-35) were incubated with asON and control ON in the presence of a cationic lipid in monolayer cell culture. To test Ki-67 as a target for antitumour therapy in more complex models, asON were administered to three-dimensional RCC (SK-RC-35) spheroid cultures and to SCID mice bearing subcutaneous SK-RC-35 xenografts. For animal studies, 1 x 10(6) SK-RC-35 cells were implanted subcutaneously. Subsequently, asON or ON were injected intraperitoneally daily for 14 days at 10 mg/kg/day. Tumour size, weight and status of metastasis were documented daily and after death, respectively. The number of apoptotic cells, Ki-67-positive cells and the microvessel density in tumour sections was determined immunohistochemically. Quantitative reverse transcription-polymerase chain reaction of Ki-67 mRNA was also assessed for the tumours. RESULTS: Treatment of RCC cells with asON resulted in a specific inhibition of cell growth in monolayer and spheroid cell culture. Systemic administration of Ki-67-directed asON significantly decreased tumour growth (P = 0.009) in SCID mice. Immunohistochemical staining of tumour specimens showed stronger inhibition of Ki-67-positive cells in asON-treated tumours (mean 27.8%) than in controls (mean 42.5-57%). Furthermore, there were about twice as many apoptotic cells after asON treatment. There was no significant difference among treatment groups for microvessel density. CONCLUSION: These results indicate that Ki-67 represents a suitable antiproliferative target, and that asON are a potent agent inhibiting tumour growth and apoptosis, but not tumour vascularization, in human RCC.
BACKGROUND: Elevation of plasma C-reactive protein (CRP) is common in patients with renal cell carcinoma (RCC). Renal tubular epithelial cells are capable of synthesizing CRP. Although production of interleukin (IL)-6 has been described in RCC, CRP expression by carcinoma cells has yet not been investigated. METHODS: In the present study we analyzed CRP plasma levels as well as intratumoral CRP and IL-6 expression of RCC from 40 patients who underwent radical nephrectomy by means of quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry. For each tumor, specimens were obtained from tumor center, tumor margin, and unaffected surrounding renal tissue. RESULTS: Preoperative plasma CRP levels correlated significantly with tumor stage (P = 0.05) and grade (P < 0.01). CRP mRNA expression was detected in 26 of 33 (79%), 30 of 36 (83%), and 32 of 36 (89%) samples from tumor center, tumor margin, and unaffected surrounding tissue, respectively. However, levels of CRP mRNA were significantly higher in tumor tissue compared to adjacent renal tissue (P < 0.01). Clear cell carcinoma exhibited significantly higher CRP mRNA levels than papillary carcinoma (P < 0.05). CRP plasma levels correlated significantly with quantitative levels of CRP mRNA within tumors (P < 0.0001). Immunohistochemically, strong CRP production was observed both in tumor cells and in tubular epithelial cells in unaffected tissue, respectively. All kidneys expressed IL-6 mRNA in the tumor and/or the unaffected tissue, but levels of intratumoral IL-6 mRNA showed no significant correlation with CRP plasma levels or local CRP transcription. CONCLUSION: In patients with RCC, a tumor-derived origin of some plasma CRP is likely. Activity of the IL-6/CRP network in RCC contributes to the accumulating evidence of the acute-phase reaction as a local inflammatory process.
Onyvax is developing Onyvax-P, an allogeneic whole-cell vaccine, for the potential treatment of prostate cancer. The vaccine is currently undergoing phase II clinical trials.
BACKGROUND: Organ-confined renal-cell carcinoma is associated with tumour progression in up to 50% of patients after radical nephrectomy. At present, no effective adjuvant treatment is established. We aimed to investigate the effect of an autologous renal tumour cell vaccine on risk of tumour progression in patients with stage pT2-3b pN0-3 M0 renal-cell carcinoma. METHODS: Between January, 1997, and September, 1998, 558 patients with a renal tumour scheduled for radical nephrectomy were enrolled at 55 institutions in Germany. Before surgery, all patients were centrally randomised to receive autologous renal tumour cell vaccine (six intradermal applications at 4-week intervals postoperatively; vaccine group) or no adjuvant treatment (control group). The primary endpoint of the trial was to reduce the risk of tumour progression, defined as progression or death. All patients were assessed after standardised diagnostic investigations at 6-month intervals for a minimum of 4.5 years. FINDINGS: By preoperative and postoperative inclusion criteria, 379 patients were assessable for the intention-to-treat analysis. At 5-year and 70-month follow-up, the hazard ratios for tumour progression were 1.58 (95% CI 1.05-2.37) and 1.59 (1.07-2.36), respectively, in favour of the vaccine group (p=0.0204, log-rank test). 5-year and 70-month progression-free survival rates were 77.4% and 72%, respectively, in the vaccine group and 67.8% and 59.3%, respectively, in the control group. The vaccine was well tolerated, with only 12 adverse events associated with the treatment. INTERPRETATION: Adjuvant treatment with autologous renal tumour cell vaccine in patients with renal-cell carcinoma after radical nephrectomy seems to be beneficial and can be considered in patients undergoing radical nephrectomy due to organ-confined renal-cell carcinoma of more than 2.5 cm in diameter.
In this paper, results from current randomized and other relevant studies on cytokine and vaccine therapy of kidney cancer in the adjuvant setting and in metastatic disease are reviewed. Improvement of medical therapy of kidney cancer is required since the relative 5-year survival of kidney cancer is only 62%. In the adjuvant setting, cytokine monotherapy (interferon [IFN]-alpha or interleukin [IL]-2) is not effective in improving progression-free or overall survival. Recently, an autologous kidney cancer cell vaccine has been shown to reduce the risk of tumor progression following radical nephrectomy for organ-confined or locally advanced kidney cancer in a randomized Phase III study. There were only a few vaccine-related side effects. Presently, this is the only promising approach for the adjuvant treatment of kidney cancer following nephrectomy. In metastatic kidney cancer patients with the tumor-bearing kidney in situ, a combination of radical nephrectomy plus IFN-alpha is more effective than IFN-alpha alone. In metastatic kidney cancer without the option of operative removal of the primary tumor and/or metastases, cytokines such as IFN-alpha, IL-2 and IL-12 and their combinations result in response rates of 10-30%, but the 5-year overall survival is less than 10%. Furthermore, the ideal dose, administration and combination of different agents are yet to be defined. Vaccine therapy of metastatic kidney cancer has been investigated only in Phase I and II studies with limited clinical benefit. Based on the current literature there is a clear need for new approaches in metastatic kidney cancer.
Therion Biologics is developing PROSTVAC, an immunotherapeutic vaccine that targets prostate-specific antigen, for the potential treatment of prostate cancer. In February 2000, phase II trials had commenced. By October 2001, the drug was undergoing four phase II trials.
MLN-591 is a monoclonal antibody specific for prostate-specific membrane antigen that is being developed by Cornell University, BZL Biologics, ImmunoGen Inc and Millennium Pharmaceuticals Inc for the potential treatment of prostate cancer. MLN-591 was in phase II trials by May 2002.
Flavopiridol is a semi-synthetic flavone analog of the alkaloid, rohitukine, a compound from an Indian tree, Dysoxylum binectariferum. It has been shown to inhibit cyclin-dependent kinases (CDKs), causing cell cycle arrest and growth inhibition. Flavopiridol is reported to have cytotoxic activity against a wide range of cancer cell lines and has demonstrated its efficacy in several clinical trials. Flavopiridol seems a well-suited potential new agent for the treatment of bladder cancer. We, therefore, evaluated whether flavopiridol inhibits growth and induces apoptosis in bladder cancer cells and additionally examined the toxicity and efficacy of this drug in vivo in a rat bladder cancer model. The in vitro experiments showed an IC20 of 50-100 nM in all cell lines tested. However, there was a difference in the response with regard to the grading of the tumor cells at higher doses. The IC50 was found to be 150-350 nM in the well-differentiated RT4 and RTI12 cell lines after treatment with flavopiridol, in comparison to a IC50 of 1000 nMfor the poorly-differentiated cell lines T24 and SUP. After exposure to flavopiridol, all tumor cell lines underwent significant apoptosis in comparison to untreated cells, beginning at a dose of 50 nM flavopiridol. At high concentrations (500 nM) of flavopiridol, 80-90% of all cells showed severe apoptotic alterations. The treatment of rat urinary bladder cancer with flavopiridol demonstrated the best efficacy with an intermittent treatment of 0.1 mg/kg, 3 times weekly over a total of 3 weeks, resulting in 7/12 animals tumor-free and a trend for the remaining tumors to have lower stage and grade. There seems to be a small advantage in intermittent versus daily application of flavopiridol. In summary, our results indicated that flavopiridol could be a useful therapeutic agent for bladder cancer, inhibiting tumor growth, malignant progression and inducing apoptosis.