Send Orders for Reprints to reprints@benthamscience.net Current Medicinal Chemistry, 2014, 21, ????-???? 1 0929-8673/14 $58.00+.00 © 2014 Bentham Science Publishers Bladder Cancer: Innovative Approaches Beyond the Diagnosis R. Piergentili 1 , S. Carradori * ,2 , C. Gulia 3 , C. De Monte 2 , C. Cristini 3 , P. Grande 3 , E. Santini 3 , V. Gentile 3 and G.B. Di Pierro* ,3 1 Istituto di Biologia e Patologia Molecolari del CNR; Dipartimento di Biologia e Biotecnologie, Sapienza - Università di Roma; Rome, Italy; 2 Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza - Università di Roma; Rome, It- aly; 3 Dipartimento di Scienze Ginecologico-Ostetriche e Scienze Urologiche, Sapienza - Università di Roma; Rome, Italy Abstract: Bladder carcinoma (BC) is the most common urinary malignant tumor. In the light of the unsuccessful current therapies and their side effects, new pharmacological strategies are needed. In addition to the well known therapeutic pos- sibilities described in the first section, we focused our attention on very recent and innovative tools to approach this target (new drug candidates from epigenetic modulators to endothelin receptor inhibitors, improved technological formulations, active principles from plants, and dietary components). Then, in the last paragraph, we analyzed the etiology of recurrent BC, with particular attention to cellular microenvironment. In fact, the incidence of recurrence is up to 90%, and 25% of tumours show progression towards invasiveness. Keywords: Bladder cancer, gene therapy, endothelin receptors, targeted therapy, histone deacetylase inhibitors, plant-derived extracts, “field cancerization” recurrence, selective COX-2 inhibitors, Peroxisome Proliferator-Activated Receptor  agonists. 1. BLADDER MALIGNANT TUMOR: AN OVERVIEW Bladder carcinoma (BC) is the most common urinary ma- lignant neoplasm with a ratio of male to female of 3.8 to 1.0 [1]. Most patients are elder than 60 years of age but BC may affect also younger patients. The most common risk factors are patient’s age, active and passive tobacco smoking [2-4], and work-related exposure to chemicals [5], schistosomiasis [6], and familiarity [7]. Haematuria is the most common sign in BC, sometimes associated to strangury, bladder tenesmus, higher risk of urinary tract infections and pollakiuria. Patho- logic staging [8, 9] depends on the presence or absence of invasion into the bladder wall. Non-muscle Invasive (Superficial) Bladder Cancer (NMIBC) Tumors which belong to stages Ta and T1 can be taken away through transurethral resection (TUR) which may also be used as a diagnostic tool to classify patients as having non-muscle invasive (superficial) bladder cancer (including carcinoma in situ, CIS, or rather high-grade tumours close to the mucosa) and muscle invasive tumours (Table 1). Patients with TaT1 tumours may also be divided into three risk groups on the description of prognostic factors: low-, inter- mediate-, and high-risk group [10]. Notably, recurrence and progression risks are two independent variables; indeed, even though prognostic factors could indicate a high *Address correspondence to these authors at the Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza - Università di Roma; Rome, Italy; Tel/Fax: +39 0649913923; E-mail: simone.carradori@uniroma1.it and Di- partimento di Scienze Ginecologico-Ostetriche e Scienze Urologiche, Sapi- enza - Università di Roma; Rome, Italy; Tel/Fax: +39 0649913923; E-mail: gb.diperro@libero.it percentage for recurrence, the progression risk could still be low. Consequently, with the purpose of distinguishing the short- and long-term risk levels of both recurrence and pro- gression in individual patients, the European Organization for Research and Treatment of Cancer proposed a scoring system with the corresponding risk tables [11]. This system has been built on the six most relevant clinical and patho- logical factors such as number of tumours, tumour size, prior recurrence rate, T category, presence of concomitant CIS and tumour grade. TUR by itself could fully eradicate a TaT1 tumour, none- theless recurrence occurs in up to 50% of patients, and pro- gression to muscle invasiveness may affect up to 10-15% of patients; consequently, it is often necessary to perform a cystoscopy after 3 months [11-15]. In these cases it is impor- tant to evaluate adjuvant therapy as intravesical chemother- apy (mitomycin C, epirubicin, and doxorubicin) or immuno- therapy (bacillus Calmette-Guérin, or BCG) instillations in order to prevent or decrease recurrence and/or progression. Moreover, therapy with BCG failed if: (i) muscle invasive tumour is detected during the follow-up; (ii) whenever high- grade, non-muscle invasive tumour is still detectable at both 3 and 6 months [16], although in patients with tumour at 3 months, an additional BCG course could exert a final re- sponse in more than 50% of cases, both in patients with pap- illary tumours and CIS [16, 17]; (iii) any worsening of the disease during BCG treatment, such as a higher number of recurrences, higher T or higher grade, or appearance of CIS, despite an initial response. The subsequent follow up is based on the specific risk class for progression/recurrence. Patients with tumours at low risk of recurrence and progression should have a