THE ROLE OF INTRAVESICAL GLYCOSAMINOGLYCANS IN TOXICITY INDUCED BY ADJUVANT INTRAVESICAL THERAPY: GENETIC LABORATORY EVIDENCE

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Abstract

Introduction and Objectives: The intravesical administrationof hyaluronic acid and chondroitin sulphate solution (HA-CS)has been proven active in patients affected by interstitialcystitis (1). The gene expression of fibronectin (FN) in bladderwashings has recently been correlated with local toxicity ofadjuvant intravesical therapy (2). The aim of the study was toinvestigate the genetic evidence of the healing or protectiveaction that HA-CS could carry out also in patients sufferingfrom topical toxicity induced by intravesical adjuvant therapygiven for non-muscle invasive bladder cancer. Materials andMethods: The study included 50 patients submitted to adjuvantintravesical therapy with mitomycin, epirubicin or bacillusCalmette–Guérin (BCG). Ten age-matched healthy patientswere enrolled as control group. Before, during and afterintravescical therapy, bladder washing samples were collectedto investigate the gene expression of FN. In 9 more patientsthe samples were collected also immediately before and aweek after the instillation of HA-CS. Topical toxicity wasclassified into 3 grades: 0-1, light (no medical therapy); 2,moderate (medical therapy); 3, severe (instillation postponed).Bladder washing samples were analyzed by isolation ofcellular RNA using a miRNeasy Mini Kit (Qiagen®). RT-PCRwas performed in order to analyze FN gene expression.Changes in the FN content were calculated using the ΔΔCtmethod after normalization with endogenous reference 18srRNA and calibrating Ct value for each RNA obtained fortriplicate reactions. Statistical analysis was performed tocorrelate the FN gene expression to tumor characteristics,treatment, topical toxicity and intravesical administration ofHA-CS. Results: FN median value before the adjuvanttreatment was 1.1-fold, with higher levels in patients withmultiple tumors (median FN=1.5; mean=3.9; p=0.0003).Twenty patients (34%) showed grade 2-3 toxicity. Comparedto controls (FN=1), FN increased during therapy a median of4-fold (range=0.2-45.2; mean=7.5) in presence of grade 2-3 toxicity, remaining stable in asymptomatic patients (medianFN=0.6; range=0.1-3.2), with a statistically significantdifference (p=0.0005). In 9 patients, one week after singleinstillation of HA-CS, the median FN gene expressiondecreased from 3.2 to 0.33 with concomitant symptomaticrelief. Discussion and Conclusion: Fibronectin is afundamental element for the repair of urothelial damage. FNgene is probably activated by the need of fibronectin forhealing process and down-regulated by the integrity of bladderurothelium. In our preliminary experience FN gene expressionin bladder washings resulted strictly related to local toxicityinduced by intravesical therapy. It increases after transurethralresection (TUR) of multiple tumors due to the greaterurothelial damage. It increases also during intravesical therapyreaching the highest levels in case of severe toxicity due to theextensive urothelial damage. A single instillation ofintravesical hyaluronic acid and chondroitin sulphate solutioninduces a rapid reduction of FN gene expression levels,particularly when high levels are present. The FN gene downregulationinduced in patients with toxicity is due tointravesical therapy and might represent an objective andmeasurable indicator of the healing activity of intravesicalinstillation of HA-CS.1 Van Agt S et al: Treatment of interstitial cystitis byintravesical instillation of hyaluronic acid: A prospectivestudy on 31 patients, Prog Urol 21: 218-225, 2011.2 Serretta V et al: Fibronectin (FN), Epidermal GrowthFactor-Receptor (EGF-R) and Heparin-Bi
Original languageEnglish
Pages3619-3619
Number of pages1
Publication statusPublished - 2015

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