chondroitin-sulfates and Urinary-Bladder-Neoplasms

Local adverse effects are the most common clinical issues in patients with bladder cancer receiving intravesical BCG immunotherapy. The aim of this systematic review was to present available options for prevention and treatment of cystitis symptoms related to bacillus Calmette-Guérin (BCG) intravesical instillations. A literature search within the Medline database was conducted in June 2018 with the following search terms: adverse events, Bacillus Calmette-Guerin, BCG, bladder cancer, cystitis, dose, dwell time, dysuria, frequency, intravesical instillations, haematuria, pain, side effects, toxicity and urgency. Eighteen relevant original articles were identified, including 15 randomized controlled trials. Potentially effective options to prevent symptoms of cystitis are BCG dose reduction, intravesical hyaluronic acid instillations and oral prulifloxacin or ofloxacin administration. For the treatment of BCG-related cystitis, available options include oral pentosan polysulphate or a combination of intravesical hyaluronic acid and chondroitin sulphate. The included studies were characterized by high heterogeneity in terms of BCG strains, schedules and endpoints. Studies on treatment of BCG-related cystitis included only small number of patients. Studies on directed medical interventions did not consider the influence on the BCG efficacy. Among few proposed preventive or therapeutic options for symptoms of cystitis related to BCG, none was proven to be both definitively effective and oncologically safe.

Topics: Adjuvants, Immunologic; Administration, Intravesical; BCG Vaccine; Chondroitin Sulfates; Cystitis; Humans; Hyaluronic Acid; Immunotherapy; Randomized Controlled Trials as Topic; Urinary Bladder Neoplasms

We investigated the efficacy of intravesical instillations of combined hyaluronic acid (HA) and chondroitin sulphate (CS) in patients with bacillus Calmette-Guérin (BCG)-induced chemical cystitis unresponsive to first-line therapies.. We retrospectively reviewed the clinical records of patients with grade 2 BCG-induced chemical cystitis unresponsive to first line therapeutic options performed according to the International Bladder Cancer Group guidelines who underwent intravesical instillations of HA/CS. Bladder pain, urinary urgency, voiding volume and number of voids/24 hours recorded prior to treatment, at the end of the treatment, at six months and at one-year follow-up were recorded and analyzed.. The records of 20 patients were identified. All patients underwent eight weekly instillations of HA/CS. Mean baseline visual analogue scale (VAS) scores ± Standard Deviation (SD) for urinary urgency and bladder pain were 7.8 ± 0.5 and 7.2 ± 1.0, respectively. Mean number of voids/24 hours ± SD was 15.4 ± 2.3 and mean urine volume per void ± SD was 85.8 ± 21.0 mL. At the end of the treatment, mean VAS scores ± SD for urgency and pain significantly decreased to 4.7 ± 1.1 and 4.2 ± 0.9, respectively (p < 0.05 in both cases). Mean number of voids/24 hours ± SD decreased to 9.6 ± 1.4 (p < 0.05) and mean urine volume per void ± SD significantly increased to 194.1 ± 59.5 mL (p < 0.05). At six months and one-year followup, all outcome measures remained stable.. Bladder instillations of HA/CS provide significant and durable improvement of bladder pain, urinary urgency, urinary volume per void and urinary frequency in patients with refractory BCG-induced chemical cystitis.

Topics: Administration, Intravesical; Aged; BCG Vaccine; Chondroitin Sulfates; Cystitis; Female; Follow-Up Studies; Humans; Hyaluronic Acid; Immunotherapy; Male; Middle Aged; Pain; Pain Measurement; Retrospective Studies; Urinary Bladder Neoplasms; Urodynamics

Although cisplatin-based neoadjuvant chemotherapy (NAC) improves survival of unselected patients with muscle-invasive bladder cancer (MIBC), only a minority responds to therapy and chemoresistance remains a major challenge in this disease setting.. To investigate the clinical significance of oncofetal chondroitin sulfate (ofCS) glycosaminoglycan chains in cisplatin-resistant MIBC and to evaluate these as targets for second-line therapy.. An ofCS-binding recombinant VAR2CSA protein derived from the malaria parasite Plasmodium falciparum (rVAR2) was used as an in situ, in vitro, and in vivo ofCS-targeting reagent in cisplatin-resistant MIBC. The ofCS expression landscape was analyzed in two independent cohorts of matched pre- and post-NAC-treated MIBC patients.. An rVAR2 protein armed with cytotoxic hemiasterlin compounds (rVAR2 drug conjugate [VDC] 886) was evaluated as a novel therapeutic strategy in a xenograft model of cisplatin-resistant MIBC.. Antineoplastic effects of targeting ofCS.. In situ, ofCS was significantly overexpressed in residual tumors after NAC in two independent patient cohorts (p<0.02). Global gene-expression profiling and biochemical analysis of primary tumors and cell lines revealed syndican-1 and chondroitin sulfate proteoglycan 4 as ofCS-modified proteoglycans in MIBC. In vitro, ofCS was expressed on all MIBC cell lines tested, and VDC886 eliminated these cells in the low-nanomolar IC. Targeting ofCS provides a promising second-line treatment strategy in cisplatin-resistant MIBC.. Cisplatin-resistant bladder cancer overexpresses particular sugar chains compared with chemotherapy-naïve bladder cancer. Using a recombinant protein from the malaria parasite Plasmodium falciparum, we can target these sugar chains, and our results showed a significant antitumor effect in cisplatin-resistant bladder cancer. This novel treatment paradigm provides therapeutic access to bladder cancers not responding to cisplatin.

Topics: Animals; Antigens, Protozoan; Antineoplastic Agents; Biomarkers, Tumor; British Columbia; Cell Death; Cell Line, Tumor; Chondroitin Sulfates; Cisplatin; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Europe; Gene Expression Regulation, Neoplastic; Humans; Inhibitory Concentration 50; Kaplan-Meier Estimate; Mice; Oligopeptides; Time Factors; Treatment Outcome; Tumor Burden; Urinary Bladder Neoplasms; Xenograft Model Antitumor Assays

Non-muscle invasive bladder cancer is the most common type of bladder cancer in Western countries. The glycosaminoglycan (GAG) layer at the bladder surface non-specifically blocks the adherence of bacteria, ions and molecules to the bladder epithelium and bladder cancer cells express CD44 that binds GAG. Currently, there are few options other than cystectomy for the management of non-muscle invasive bladder cancer with intravesical chemotherapy using several drugs such as gemcitabine (GEM) and mitomycin-C (MMC) with poor prophylactic activity. In this study, we investigated the effects of the GAG chondroitin sulphate (CS) on the growth inhibition of human bladder cancer cell lines HT-1376 and effects of the combination between GEM or MMC with CS. We have found that CS, MMC and GEM induced 50% growth inhibition at 72 h. Therefore, we have evaluated the growth inhibition induced by different concentration of CS in combination with MMC or GEM, respectively, at 72 h. We have observed, at Calcusyn analysis, a synergism when HT-1376 cells were treated with CS in combination with MMC or GEM, respectively, if used at an equimolar ratio. We have also found that CS/GEM combination induced a strong potentiation of apoptosis with the consequent activation of caspases 9 and 3. On the other hand, HT-1376 cells were necrotic if exposed to the CS/MMC combination and no signs of caspase activation was observed. In conclusion, in the human bladder cancer cell line HT-1376 pharmacological combination of CS with GEM or MMC resulted in a strong synergism on cell growth inhibition.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Caspases; Cell Line, Tumor; Cell Proliferation; Chondroitin Sulfates; Deoxycytidine; Drug Synergism; Enzyme Activation; Gemcitabine; Humans; Mitomycin; Urinary Bladder Neoplasms

Twenty seven bladder tumors, three ureteral tumors and one renal pelvic tumor were studied by means of light microscopic histochemical methods for demonstration and identification of acid mucopolysaccharides. Alcian blue (pH 1.0), alcian blue (pH 2.5), periodic acid-Schiff (PAS) and aldehyde-fuchusin stainings were performed. These stainings showed that all tumor specimens contained acid mucopolysaccharides. For identifying individual acid mucopolysaccharides, enzyme digestion procedures were performed prior to staining with alcian blue. (streptomyces hyaluronidase, testicular hyaluronidase, chondroitinase ABC, chondroitinase AC, keratanase, heparinase, heparitinase.) According to these experiments, high-grade, and high-stage tumors contained large amounts of sulfated mucopolysaccharides. Squamous cell carcinomas of the bladder contained especially large amounts of chondroitin sulfate AC.

Topics: Aged; Alcian Blue; Carcinoma, Squamous Cell; Chondroitin Sulfates; Female; Glycosaminoglycans; Histocytochemistry; Humans; Kidney Neoplasms; Male; Middle Aged; Ureteral Neoplasms; Urinary Bladder Neoplasms

The glycosaminoglycans of four normal human bladders and fourteen bladder cancers were characterized and quantitated (after proteolytic extraction) by specific enzyme digestion, cellulose acetate electrophoresis and densitometry. Hyaluronic acid, heparan sulfate, dermatan sulfate and chondroitin sulfate were identified in both normal and cancerous bladders. Hyaluronic acid and dermatan sulfate were the major glycosaminoglycans of the normal epithelium/submucosa while heparan sulfate and dermatan sulfate were predominant in normal bladder muscle. Bladder cancer glycosaminoglycan content was influenced by the stage and grade of the neoplasm. Hyaluronic acid and dermatan sulfate tended to decrease and chondroitin sulfate to increase in infiltrating cancers, whereas a decrease in the percentage of heparan sulfate correlated closely with higher grade tumors. The bladder cancer glycosaminoglycan profile may be indicative of the tumor's invasive potential.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Child; Chondroitin Sulfates; Densitometry; Electrophoresis, Cellulose Acetate; Female; Glycosaminoglycans; Heparitin Sulfate; Humans; Hyaluronic Acid; Male; Middle Aged; Urinary Bladder; Urinary Bladder Neoplasms

Urinary glycosaminoglycan excretion was examined in 25 individuals with bladder cancer in comparison to glycosaminoglycan excretion by eight normal individuals. Urinary glycosaminoglycan was isolated by gel filtration and quantified as macromolecular uronate concentration. Electrophoresis in calcium acetate and densitometry of Alcian blue-stained electrophoretograms were used to separate and quantify the relative amounts of individual glycosaminoglycans. Elevated excretion of macromolecular uronate was noted in 53% of the cancer cases. The highest levels were found among individuals with metastatic disease. Three electrophoretic bands were always detected in the control and cancer groups: chondroitin sulfate, heparan sulfate (both confirmed by chemical and enzymatic degradation), and a third band (Band 1) of unknown composition. A fourth band, corresponding to dermatan sulfate, was seen in some high-grade metastatic tumors. Band 1 excretion was elevated in a significant fraction of all patients. Seven of 12 metastatic cases but only two of 13 localized cases showed increased heparan sulfate excretion. Diagnostic limits were drawn from the observed distributions of normals, and with these limits 92% of the cancer cases, including 12 of 12 metastatic cases, could be identified. The results strongly suggest noninvasive urinary glycosaminoglycan analysis may well provide a new biochemical approach for detecting and monitoring the pathogeneses of bladder cancer.

Topics: Chondroitin Sulfates; Dermatan Sulfate; Electrophoresis; Glycosaminoglycans; Heparitin Sulfate; Humans; Macromolecular Substances; Neoplasm Metastasis; Urinary Bladder Neoplasms; Uronic Acids