BBN as an Urothelial Carcinogen

Experimental urinary bladder tumours have been proposed as a useful model for the study of urinary bladder carcinogenesis, as well as for evaluating new therapeutic strategies. Consequently, the administration of chemical carcinogens is one of the most commonly used methods for inducing urinary bladder tumours. N-butyl-N-(4hydroxybutyl)nitrosamine (BBN) is, undoubtedly, the mostused urothelial chemical carcinogen. BBN belongs to the nitrosamine family, a wide group of alkylating agents that are able to induce bladder tumours in laboratory animals. Depending on the animal species, the spectrum of urothelial lesions induced by BBN varies, but is similar to those observed in humans. BBN has a high propensity to induce mutations affecting the expression of genes such as p53, RAS and H19 among others. The aim of this study was to review BBN as a urothelial tumour inducer, taking into consideration its chemical characteristics, properties and spectrum of lesions induced, as well as its possible applications. Bladder cancer is among the most common malignancies worldwide, and it assumes greater prominence in developed countries. The most recent data, published in 2011, showed an estimated 386,300 new cases and 150,200 deaths in 2008. Bladder cancer is the second-most common tumour of the genitourinary tract and the second-most common cause of death in patients with genitourinary tract malignancies (1). In humans, the most common cell type of bladder cancer is transitional cell carcinoma, although adenocarcinomas, squamous cell carcinomas and sarcomas can also occur (2). The majority of patients with bladder cancer, 75-85%, are diagnosed with superficial tumours, while the remaining 15% to 25% have invasive ones (2, 3). The superficial ones are low-grade, well-differentiated papillary tumours that do not invade or metastasize. Histological evolution in this case starts as hyperplasia, evolving to papilloma, papillary urothelial neoplasms of low malignant potential and papillary carcinoma (lowand high-grade) (4). The invasive tumours originate as flat lesions such as hyperplasia, dysplasia and carcinoma in situ that then evolve into invasive carcinomas (5). These are high-grade tumours that frequently have areas of squamous cells or glandular differentiation or areas of undifferentiated tumour, including small-cell or spindle-cell variations. Invasive tumours are devastating, since over 50% of the patients will die from metastatic disease (2). Experimental Models of Bladder Cancer The need for experimental models of tumours that are as similar as possible to those in humans has prompted researchers to attempt various approaches. Animals such as dogs, rabbits, guinea pigs and hamsters have all been used in the past to study urinary bladder carcinogenesis (6). However, for ethical reasons and due to the conditions in animal facilities, dogs cannot be used in experimental models of carcinogenesis. Animal facilities in order to maintain guinea pigs and rabbits also require special equipment, making models difficult to apply. For these reasons, small rodents, such as mice and rats, are the most common species used. These animals have a lower urinary tract that is comparable to that of humans, and neoplasms in their bladders are morphologically very alike (7). On the other hand, in most strains of rodents, bladder cancer is not commonly found unless a chemical or other treatment is applied (8). Another advantage is associated with the fact that these are small animals and there is an abundance of information concerning the biological characteristics of neoplastic development in these species (6). Mouse strains such as BALBC, C57BL and 727 Correspondence to: P.A. Oliveira, Agrarian School of Viseu, Polytechnic Institute of Viseu, Viseu, Portugal. E-mail: pamo@utad.pt