Cellular fibronectin in patients with transitional cell carcinoma of the bladder

Various tumor markers for transitional cell carcinoma (TCC) of the bladder have been described, but none of them are used in clinical routine. Fibronectin, a glycoprotein, seems to play a very important role in both the progression and invasion of cancer. The aim of this study was to evaluate cellular fibronectin (cFN) in the urine and blood of patients with TCC of the bladder and to determine its possible role as a tumor marker and prognostic factor. Morning urine samples and blood were collected from 20 patients (8 women, 12 men, mean age 69.9 years) before they underwent transurethral resection of bladder tumors (TURB). Twenty patients (10 women, 10 men, mean age 63.4 years) with nonmalignant urological disorders were recruited as the control group. Determination of cFN in plasma and urine was performed by using a newly developed time-resolved fluorescence immunoassay (TRFIA). Patients with nonmalignant diseases had mean cFN plasma levels of 404 ng/ml (range 181-746 ng/ml). Patients with TCC of the bladder showed significantly higher cFN plasma levels of 686 ng/ml (range 274-1999 ng/ml, p<0.05). Subdivided according to the TNM system, muscle-invasive bladder tumors (n=5) demonstrated higher cFN plasma levels (mean 944 ng/ml) than superficial bladder tumors (n=15, mean 463 ng/ml). There were no differences of plasma cFN concentrations concerning tumor grade and also no differences in urine levels between the different groups. We found a significant difference (p<0.04) of cFN plasma levels between patients with TCC of the bladder and the control group. The difference in cFN plasma levels between pTa/pT1 and >or=pT2 tumors indicates a clinically useful potential of this tumor marker for preoperative staging and postoperative follow-up. Our data underline the important but still unclear role of cFN as a tumor marker in TCC, and this will be the focus of future studies.     

Serotonin used as prognostic marker of urological tumors

Introduction  In regard to therapy and prognosis of urological tumors, specific tumor markers are lacking especially in renal and urinary bladder carcinoma. Our study examines the relevance of serum serotonin levels to urinary bladder, prostate, renal, and testicular carcinoma when it comes to prognosis and occurrence of these oncological conditions. Materials and methods  Serotonin levels were obtained in 109 patients presenting with urothelial carcinoma to the urinary bladder, adenocarcinoma of the prostate and renal cell carcinoma, as well as presenting with seminomatous and non-seminomatous testicular tumors. All of these conditions varied in grades and metastases. Serum levels were drawn between 7 and 8 a.m. exclusively in order to avoid circadian changes. Results  Serotonin levels in urothelial carcinoma appeared within pathological range in correlation with tumor stage, life expectancy, and statistical significant with distant metastases. In prostate carcinoma, serotonin levels showed a tendency with organ exceeding growth, Grading/Gleason Score, PSA values >100 ng/ml, and the presence of distant metastases. In renal cell carcinoma, serotonin levels were decreased in patients with lymph node and distant metastases; there was no significant correlation with extent of infiltration. In regard to testicular carcinoma, decreased serotonin levels were merely noted in mixed tumors and the one extragonadal seminoma. Otherwise there was no correlation observed with stage and grade as well as with common tumor markers (AFP/βHCG). Conclusion  Serotonin levels are suitable for prognostic evaluation of urothelial carcinoma in the urinary bladder, adenocarcinoma of the prostate, and renal cell carcinoma, especially taking into account the lab cost of 25€ per test.     

Significance of tissue laminin P(1) elastase and fibronectin levels in transitional cell carcinoma of the bladder

OBJECTIVE: Elastase is a serine protease which hydrolyses connective tissue components. Laminin and fibronectin also play an important role in progression and invasion of cancer. The purpose of this study is to investigate the relation between tissue elastase, laminin P(1) and fibronectin levels and tumor characteristics, and analyze the potential of these as prognostic factors in transitional cell carcinoma (TCC) of the bladder. METHODS: Thirty-four patients with TCC of the bladder and 11 controls were included in this study. Elastase and fibronectin levels in tissue homogenates were determined using an enzyme immunoassay and laminin P(1) by radioimmunoassay. Mean follow-up was 43 months. RESULTS: The mean elastase level in bladder carcinoma tissue was 120+/-11.42 ng/homogenate protein, while normal tissue level was 12.36+/-2.70 (p<0.01). The carcinoma and normal tissue mean laminin P(1) levels were 7.02+/-0.37 U and 0.65+/-0.10 U/mg homogenate protein, respectively (p<0.01). The mean fibronectin level was 19.97+/-1.45 ng/mg homogenate protein in the carcinoma tissue and 2.16+/-0.40 in normal tissue (p<0.01). There was no correlation between tumor stage, grade, size, multiplicity and elastase, laminin P(1) and fibronectin levels. CONCLUSION: These results provide evidence that tissue elastase, laminin P(1) and fibronectin levels increase in TCC of the human bladder. Further studies including serum and urine levels should be performed in order to analyze their value as tumor markers in a larger group of patients.     

A case of transitional cell carcinoma of renal pelvis with an extremely high serum carcinoembryonic antigen (CEA) level]

A case of urothelial tumor with extremely high serum carcinoembryonic antigen (CEA) levels is described. A 68-year-old female presented with macroscopic hematuria and left flank pain. Laboratory examination revealed an extremely high serum level of CEA (194 ng/ml) and elevated levels of serum CA 19-9 (235 U/ml) and squamous cell carcinoma (SCC)-Antigen (10.7 ng/ml), while urine CEA remained within normal limits. No abnormal findings were recognized in gastrointestinal and respiratory systems, but left renal pelvic tumor (T4N2M0) was discovered. Nephroureterectomy with regional lymph node dissection was done. The pathologic anatomy was infiltrating non-papillary transitional cell carcinoma (TCC, G2 = G3, pT4N2M0). More than 30% of the tumor cells were positive for CEA by ABC-peroxidase staining. Levels of tumor markers remained higher than normal after the operation and were normalized after M-VAC (methotrexate, vinblastine, adriamycin and cisplatin) chemotherapy. However, 6 months after the operation, levels of tumor markers rose again and lung metastases appeared. She died 10 months after the operation.     

AFP-producing urothelial carcinoma of the bladder: a case report

We report a case of urothelial carcinoma of the urinary bladder with concurrent alpha-fetoprotein (AFP) elevation. A 60-year-old male was admitted for gross hematuria. Subsequent analyses revealed elevated serum AFP levels (970.20 ng/ml). He had no history of hepatitis, and hepatobiliary disease was not detected on computed tomography or ultrasound. Carcino-embryonic antigen was normal. The patient underwent radical cystectomy and was found to have a high-grade urothelial carcinoma of bladder on pathology. In addition, immunohistochemical staining of the tumor cells showed strong AFP positivity. Postoperatively, serum AFP levels decreased gradually to normal. In summary, urothelial carcinoma of the urinary bladder with AFP elevation is rare, and the mechanism and prognosis require further exploration.     

Plasma levels of CEA as a prognostic marker in carcinoma of urinary bladder.

Plasma carcinoembryonic antigen (CEA) levels were performed preoperatively by radioimmunoassay in 124 patients with histologically proved bladder carcinoma. The level of CEA was used to determine its prognostic value in patients with bladder cancer. The correlation of CEA levels with the stage of the disease, histology, and resectability was also studied. Values above 2.5 ng/ml were taken as abnormal. Active disease was associated with high CEA levels. All patients with CEA levels greater than 10 ng/ml died in less than 1 1/2 years, while all patients who survived 1 1/2-3 years had preoperative CEA levels less than 10 ng/ml. There was a prognostic significance for patients with transitional cell or squamous cell carcinoma. All patients with squamous cell carcinoma had CEA levels less than or equal to 10 ng/ml, and all patients with transitional carcinoma had preoperative CEA values greater than 10 ng/ml. A correlation between CEA levels and resectability of the primary tumor was found. This study indicates that, in bladder carcinoma patients, preoperative CEA levels greater than 10 ng/ml are of prognostic value, since all of these patients have died and all of the long-term survivors had levels of less than or equal to 10 ng/ml.     

Measurement of serum circulating intercellular adhesion molecule-1 and its clinical significance in hepatocellular carcinoma: preliminary report

Serum circulating intercellular adhesion molecule-1 (cICAM-1) was measured in 50 patients with hepatocellular carcinoma (HCC). The mean cICAM-1 level in the 50 patients was 2220 ng/ml and 43 patients (86%) had a high level of cICAM-1 — more than 1000 ng/ml. Comparative analysis of cICAM-1 and alpha-fetoprotein (AFP) levels in the HCC patients showed that serum AFP level was negative (<20 ng/ml) in five patients or "questionable positive" (20–90 ng/ml) in ten patients, while the levels of cICAM-1 in these patients were 1810 and 1710 ng/ml, respectively. Seven patients who underwent hepatectomy had tumor recurrences during a follow-up period of 6–18 months. Their serum AFP levels were lower than 200 ng/ml (mean value, 27 ng/ml), but their mean cICAM-1 level was 1956 ng/ml at the time tumor recurrence was diagnosed. We suggest that the measurement of serum cICAM-1 is not only useful for prediction of the progression and prognosis of HCC, but that it may also be an important marker for the early diagnosis of the disease, and for monitoring postoperative recurrence, particularly in patients with low levels of serum AFP. Received for publication on Aug. 24, 1998; accepted on Jan. 4, 1999     

A prostatic duct carcinoma difficult to distinguish from transitional cell carcinoma: a case report

A 77-year-old male with a complaint of dysuria and gross hematuria for 3 months visited our hospital. Abdominal ultrasonography, computed tomographic scan and magnetic resonance imaging revealed a prominent tumor from the bladder neck. Serum prostate specific antigen (PSA) level was high (1,130 ng/ml) suggesting prostate cancer, but transitional cell carcinoma (TCC) was detected by transurethral biopsy. Bone scintigraphy revealed multiple bone metastasis. Since gross hematuria requiring bladder tamponade continued, simple cystoprostatectomy and cutaneous ureterostomy were performed. Pathological findings showed prostatic acinar carcinoma and prostatic duct carcinoma mimicking TCC, and PSA immunohistochemically weak positive. The final diagnosis was prostate cancer consisting of acinar and ductal component. Adjuvant hormonal therapy was performed, but was ineffective. The patient died 2.5 months after operation. We reviewed and discussed 66 cases of prostatic duct carcinoma, including our case, in the Japanese literature.     

Promoter methylation of H-cadherin is a potential biomarker in patients with bladder transitional cell carcinoma

Objectives  

H-cadherin, functions as a tumor suppressor, is frequently silenced by promoter methylation in human cancers. The aim of this study was to evaluate the feasibility of using H-cadherin methylation in tumor tissues as a potential biomarker in patients with bladder transitional cell carcinoma (TCC).     

Alterations in polymeric immunoglobulin receptor expression and secretory component levels in bladder carcinoma

Summary To assess the capacity of transitional cells to synthesize and release polymeric immunoglobulin receptor (pIg-R) in bladder carcinoma, we studied the localization of pIg-R in normal and tumor tissues and measured the levels of secretory component (SC) either in the free form or bound to Ig (S-IgA, S-IgM) in the serum and urine of 56 patients with transitional-cell carcinoma (TCC) of the bladder. In the normal bladder mucosa, pIg-R was localized in the cytoplasm and plasma membranes of the superficial cells and on all epithelial cell membranes. In TCC cases, 65% of those studied expressed pIg-R. A marked heterogeneity in pIg-R staining was observed in some tumors. Although a better expression of pIg-R in tumors with a well-preserved epithelial architecture was observed, no correlation was found between pIg-R expression and the grade or stage of the tumors in the patients under study. Three groups were established: (1) in TCC with no complications, serum levels of free SC and S-IgA were significantly increased; (2) in TCC with urinary infections (UI), serum levels of free SC and S-IgA were significantly higher than control values but lay within the same range observed in TCC with no complications and rates of urinary excretion of SC were significantly higher than those in normal subjects; (3) in TCC without UI but with hepatic disorders [high gamma-glutamyl transferase (GGT) activity], there was a correlation between serum S-IgA levels and GGT activity (r=0.5, P<0.005) and serum SC levels were significantly higher than those observed in the other groups. Whereas urinary SC levels appear to reflect urinary infection, serum SC levels, albeit influenced by the hepatic status, may be an additional marker of TCC of the bladder.     

Potential value of soluble intercellular adhesion molecule-1 in the serum of patients with bladder cancer

INTRODUCTION: The potential value of serum levels of intercellular adhesion molecule-1 (ICAM-1) in the staging and pathological nature of bladder cancer was investigated in this study. MATERIALS AND METHODS: A total of 90 patients (mean age 64.5 +/- 7.1) having transitional cell carcinoma of the bladder and 30 control patients (mean age 64.0 +/- 5.5) were enrolled in the study. The serum samples of the patients were obtained on the day before surgery, at the same hour of the day. RESULTS: The preoperative sICAM-1 levels were found to be 46.2 +/- 14.7 and 28.0 +/- 7.8 ng/ml in the tumor group and the control group respectively, which is significantly higher (p = 0.00). The ICAM-1 levels were not different in the invasive tumor group (36 patients) and the superficial tumor group (54 patients; 47.3 +/- 13.8 ng/ml in the invasive group and 45.5 +/- 15.3 ng/ml in the superficial tumor group; p = 0.520). The serum levels of sICAM-1 were significantly higher in grade III tumors than grade I and II tumors (62.0 +/- 8.7, 38.4 +/- 11.9 and 42.2 +/- 8.2 ng/ml respectively; p = 0.000). The mean serum sICAM-1 levels in tumors >3 cm and <3 cm were found to be 52.6 +/- 15.8 and 40.7 +/- 11.0 ng/ml respectively which is statistically significant (p = 0.000). CONCLUSIONS: In this study, serum ICAM-1 levels were found to be related to tumor presence, grade and size. Larger series are needed for the thorough understanding of the role of ICAM-1 in bladder cancer.     

Choriocarcinoma of the renal pelvis: a case report

A 68-year-old male presented to our hospital complaining of gross hematuria. Intravenous pyelography subsequently demonstrated a left non-visualized kidney, and he was admitted for further evaluation. Cystoscopy revealed a bladder tumor around the left ureteral orifice and retrograde pyelography showed a filling defect in the left renal pelvis. The urinary cytology from the left renal pelvis indicated class IV, and the microscopic findings of a bladder biopsy demonstrated grade 1 transitional cell carcinoma. We performed transurethral resection of bladder tumor (TUR-BT) followed by left nephroureterectomy with bladder cuff. The pathological diagnosis was high grade transitional cell carcinoma with choriocarcinomatous component. After the operation, the serum human chorionic gonadotropin-beta (hCG-beta) level was slightly elevated, and the combination chemotherapy with methotrexate, vinblastine and cisplatin (MVC) was administered. Although the serum hCG-beta level fell to 0.1 ng/ml, after two courses of MVC chemotherapy, bilateral pulmonary metastases appeared in the chest X-ray with increasing hCG-beta levels. Salvage chemotherapy with cisplatin, etoposide and bleomycin (PEB) was performed. After two courses of PEB chemotherapy, the serum hCG-beta level fell to within the normal range and all pulmonary metastases disappeared.     

LASP-1, a Novel Urinary Marker for Detection of Bladder Cancer

ObjectivesThe LIM and SH3 (LASP)-1 protein is a focal adhesion protein that has been linked to oncogenesis. The aim of this study was to evaluate the diagnostic use of the detection of LASP-1 in tumor specimens and in urine for noninvasive detection of transitional cell carcinoma (TCC).Materials and methodsImmunohistochemical staining for LASP-1 was performed on 72 archived bladder tumor specimens, and LASP-1 content was measured in 132 spontaneous urine sample sediments by Western blot analysis.ResultsIn the histologic specimens, immunohistochemical staining for LASP-1 showed abundant expression throughout the urothelium of the bladder and ureter. However, modest overexpression of LASP-1 was observed in the TCC specimens. Measurement of the LASP-1 protein concentrations in urinary cell pellets from healthy donors and bladder cancer patients was highly sensitive for the presence of TCC. The cut-off value was determined by receiver operating characteristic (ROC) analysis. When a cut-off value of 1 ng LASP-1/500 μl of urine was used, the sensitivity, specificity, and positive and negative predictive values of the assay were 83.1%, 85.3%, 83.1%, and 80.6%, respectively.The increased urinary LASP-1 content in TCC patients was attributable in part to a specific increase in cell shedding presumably caused by changes in cell adhesion, as confirmed by LASP-1 knockdown. Contamination with erythrocytes above 250 cells/μl and urinary infection gave false positive results and are therefore sample exclusion criteria.ConclusionsIn the absence of urinary infection or gross hematuria, urinary LASP-1 level is a promising marker for transitional cell carcinoma.     

The levels of glutathione peroxidase, vitamin A, E, C and lipid peroxidation in patients with transitional cell carcinoma of the bladder

OBJECTIVE: To assess the levels of erythrocyte glutathione peroxidase (GSH-Px), and the serum levels of antioxidant vitamins (A, E and C), selenium and malondialdehyde (MDA) in patients with transitional cell carcinoma (TCC) of the bladder. PATIENTS, SUBJECTS AND METHODS: The study comprised 91 people (23 healthy controls and 68 patients with TCC). Erythrocyte GSH-Px activity was measured by spectrophotometry, high-performance liquid chromatography to detect serum levels of vitamins and MDA, and fluorometry to detect serum levels of selenium. RESULTS: The serum levels of vitamin A, E and C, and selenium were significantly lower (P < 0.05) in patients with TCC than in controls. However, erythrocyte GSH-Px activities (P < 0.05) and serum MDA levels (P < 0.01) were significantly higher in patients with TCC than in the controls. CONCLUSIONS: Levels of free oxygen species were higher, and antioxidant vitamin and selenium levels lower, in patients with bladder TCC than in controls. These findings, with the results of previous animal studies, suggest that giving vitamin A, C, E and selenium may be beneficial in preventing and treating human bladder cancer.     

Risk stratification for bladder tumor recurrence, stage and grade by urinary nuclear matrix protein 22 and cytology

PURPOSE: To test the hypothesis that voided urinary levels of nuclear matrix protein 22 (NMP22) would add to the predictive ability of urine cytology in the diagnosis, staging and grading of bladder transitional cell carcinoma (TCC), and to evaluate the diagnostic performance of different NMP22 cut-points. MATERIALS: NMP22 level and barbotage cytology were evaluated in voided urine specimens collected before cystoscopy from 302 subjects with a history of TCC, 32 subjects with benign urologic pathologies, and 10 healthy volunteers. RESULTS: 180 patients (52%) had bladder TCC. Higher levels of NMP22 and positive cytology were independently associated with an increased risk of TCC, invasive stage, and high grade. The NMP22 value with equal sensitivity and specificity for prediction of bladder cancer was 6.5U/ml; for prediction of grade 3 TCC it was 13.5U/ml; and for prediction of invasive tumor stage it was 17.4U/ml. The NMP22 cut-point of 6.5U/ml outperformed the 10U/ml cut-point in all pathologic stages and grades. The diagnostic sensitivity of the cytology and NMP22 combined was superior across all pathologic stages and grades to that of either marker alone. NMP22 and cytology stratified patients into groups with significantly different risk for TCC presence, invasive stage, and high grade. CONCLUSIONS: 6.5U/ml is a robust NMP22 cut-point for bladder cancer surveillance. The diagnostic sensitivities of the combined NMP22 and cytology for TCC presence, stage, and grade were significantly higher than those of single marker alone. The combination of urine cytology and NMP22 could be used to tailor the frequency of cystoscopic follow up.     

A case report: small cell carcinoma transformed from transitional cell carcinoma of the urinary bladder

A 72-year-old man presented with gross hematuria. Cystoscopy showed a non-papillary tumor at the right side of the posterior wall. Transurethral resection of the bladder tumor (TURBT) was performed. Pathologic findings demonstrated superficial transitional cell carcinoma (TCC). However, recurrent tumors were detected at the same location after 69 months' follow up. TURBT was done for the biopsy and pathologic examination showed muscle-invasive TCC. After two courses of neoadjuvant chemotherapy (MVAC), we performed radical cystectomy with Hautmann's continent reservoir. Pathologic findings revealed small cell carcinoma without any TCC features. Immunohistochemical staining using chromogranin A and synaptophysin was positive in the latest TURBT and the radical cystectomy specimens. We report a case of primary small cell carcinoma transformed from TCC of the urinary bladder.     

Two cases of bladder tumor producing granulocyte colony stimulating factor

Two cases of bladder tumor producing granulocyte colony-stimulating factor (G-CSF) are reported. The first case was in a 79-year-old female patient. A large bladder tumor was diagnosed as right-sided hydronephrosis. The tumor consisted mostly of squamous cell carcinoma with a few transitional cells. Total cystectomy could not be performed because of direct invasion by the tumor into the pelvis. The patient died without aggressive treatment about 7 months after admission. Her leukocyte count consistently increased up to 76,200/mm3. The serum G-CSF levels were not analyzed. However, immunohistochemical examination revealed a high concentration of G-CSF in the tumor specimen. The other case was in an 80-year-old male patient. The patient, who had refused total cystectomy for bladder tumor (transitional cell carcinoma, grade 2, T2N0M0) 2 years earlier, underwent ureterocutaneostomy for obstructive renal insufficiency. Total cystectomy was not performed at this admission because of tumor invasion into the rectum and his advanced age. Radiotherapy was administered. However, he developed ileus caused by direct tumor invasion into the ileum. He died about 10 months after the urinary diversion. Leukocytosis, which improved transiently following radiotherapy, became more severe. The maximum leukocyte count was 49,500/mm3 just before death. The serum G-CSF levels during and after radiotherapy were 54 pg/ml and < 30 pg/ml, respectively. Immunohistochemical examination revealed the presence of G-CSF in the tumor. These findings suggest the production of G-CSF by the bladder tumor.     

A study of an effective sunitinib–chemotherapeutic combination regimen for bladder cancer treatment using a mouse model

ObjectiveTo determine if tyrosine kinase receptor inhibitor, sunitinib malate, combined with chemotherapeutic drugs may present synergistic enhancement of cytotoxicity to transitional cell carcinoma cells (TCC).MethodsThe mRNA and protein contents of vascular endothelial growth factor-α (VEGFα) in various TCC cell lines were detected individually by quantitative-polymerase chain reaction and Western blot. The inhibitory concentrations of various chemotherapeutic drugs, including gemcitabine, doxorubicin, and cisplatin, and their combination with sunitinib to TCC cancer cells were determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The synergist efficacy was measured using the observed/expected ratio calculation method. Finally, the synergistic effect of sunitinib and selected anticancer drug gemcitabine was elucidated in C3H/MBT-2 animal tumor model with monitoring tumor growth volume and survival rate.ResultsThe mRNA of VEGFα had high expression in high-grade TCC cell lines (T24, TCC 8701, and TCC 8702) when compared with low-grade TCC cell lines (TCC 8301 and TSGH 9201). The expression of VEGFα protein level was closely correlated with the mRNA content in each individual cell line. Sunitinib, combined with gemcitabine, has shown the highest synergistic cytotoxic effect to TCC cells in an MTT assay. In the xenografted tumor model, MBT-2 bearing mice treated by sunitinib and gemcitabine combination had the lower mean tumor volume (265 ± 95 mm³ vs. 2605 ± 320 mm³) and higher survival rate (100% vs. 56%) at 30 days follow-up when compared with control mice.ConclusionCombination of the tyrosine kinase receptor inhibitor sunitinib with gemcitabine chemotherapy synergistically enhances tumor cytotoxicity and may provide a new treatment modality for advanced bladder cancer.     

A case of primary choriocarcinoma of the bladder

A 75-year-old man visited our hospital presenting with gross hematuria. Cystoscopy revealed a bladder tumor with coagulated blood and necrotic tissue at the dome. We resected the bladder tumor transurethrally. Pathologically, the tumor was shown to be a transitional cell carcinoma with choriocarcinomatous differentiation, G3, > or = pT2. Immunohistochemical staining showed human chorionic gonadotropin (HCG)-positive tumor cells. Just after surgery, the serum HCG-beta concentration was less than 0.1 ng/ml. Total cystectomy and an ileal conduit operation were performed. The histological classification was TCC, G3, pTis. In later blood chemistry tests, HCG-beta elevation was observed. Pulmonary metastases appeared on a chest X-ray, and combination chemotherapy with cisplatin and etoposide was administered. Although the serum HCG-beta decreased with one course of chemotherapy, it increased immediately thereafter. The patient died of the disease about 8 months after the total cystectomy. Autopsy revealed multiple metastases in the lungs, liver, kidneys, stomach, pancreas, thyroid gland, adrenal glands, heart, jejunum, and vertebral body (Th10). Lymph node metastases in the pulmonary hilum, mediastinum, and right submaxillary gland were also found.     

Exposure to Vinorelbine Inhibits in Vitro Proliferation and Invasiveness of Transitional Cell Bladder Carcinoma

Purpose

To study the effect of vinorelbine (VNR) on in vitro cell proliferation, invasiveness, cell adhesion to substrate, cell motility and metalloproteinase secretion of MB-49, a murine transitional cell carcinoma of the bladder (TCC).

Materials and Methods

The colorimetric MTS assay, which depends upon viable versus nonviable mitochondria, was used to evaluate the effect of graded concentrations of VNR on in vitro MB-49 cell growth. Chemoinvasion and cell motility were studied in TCC cells exposed for 24 hours to a noncytotoxic dose of VNR, through their ability to migrate across Matrigel -coated or Type IV collagen-coated 8-micrometer. pore filters. Zymographic studies in gelatin-embedded polyacrylamide gels were done to investigate gelatinolytic activity in conditioned media from treated and untreated MB-49 cells.

Results

Vinorelbine inhibited MB-49 cell growth in a dose-dependent manner (IC₅₀ 40 ng./ml.). In vitro cell invasive capacity of MB-49 cells pretreated for 24 hours with VNR at noncytotoxic doses (1 and 10 ng./ml.) was significantly lower than that of untreated cells. The decreased invasion of VNR-treated cells was not accompanied by a diminished adhesion to Matrigel (R) or type IV collagen nor by a significant reduced secretion of gelatinolytic metalloproteinases. Instead, motility of MB-49 cells exposed to noncytotoxic concentrations of VNR was inhibited in a dose-response fashion similar to that of invasion.

Conclusion

Vinorelbine proved to be an effective drug to inhibit tumor cell growth and invasion in a transitional cell bladder carcinoma model. The results obtained would justify preclinical studies to evaluate the effectiveness of VNR as a potential treatment of TCC.