Inhibition of bladder tumor growth by chitooligosaccharides in an experimental carcinogenesis model.

Urinary bladder cancer is one of the most common cancers worldwide, with the highest incidence in industrialized countries. Patients with cancer commonly use unconventional and complementary therapy including nutraceuticals. In this study we evaluated the efficacy of chitooligosaccharides (in orange juice) in rat bladder cancer chemoprevention and as therapeutic agent, on a rat model of urinary bladder carcinogenesis induced with N-butyl-N-(4-hydroxybutyl) nitrosamine. Results indicate that chitooligosaccharides may have a preventive effect on bladder cancer development and a curative effect upon established bladder tumors, dependent on the concentration ingested 500 mg/kg b.w., every three days, showed capacity to inhibit and prevent the proliferation of bladder cancer; however, this was associated with secondary effects such as hypercholesterolemia and hypertriglyceridemia. The use of lower doses (50 and 250 mg/kg b.w.) showed only therapeutic effects. It is further suggested that this antitumor effect might be due to its expected anti-inflammatory action, as well as by mechanisms not directly dependent of COX-2 inhibition, such as cellular proliferation control and improvement in antioxidant profile.

Inhibition of bladder tumour growth by sirolimus in an experimental carcinogenesis model.

OBJECTIVE: To investigate the anticarcinogenic effects of sirolimus 2 mg/kg/day on a rat model of urinary bladder carcinogenesis induced with N-butyl-N(4-hydroxybutyl)nitrosamine (BBN). MATERIALS AND METHODS: Thirty-six male Wistar rats were divided into four groups: 1, a control group (eight), given tap water only; 2, a sirolimus control group (eight), given 2 mg/kg/day; 3, a carcinogen (BBN) group (12) exposed to 0.05% BBN; 4, a treatment group (sirolimus/BBN; eight) given 2 mg/kg/day + 0.05% BBN. In the tumour-induction phase, from week 1 to week 8, rats from groups 3 and 4 received BBN ad libitum in drinking water. In the treatment phase, from week 8 to week 20, rats from groups 2 and 4 received sirolimus 2 mg/kg/day by an oesophageal cannula. At week 20 the rats were killed humanely, and the number and size of tumours recorded. The bladders were collected for histological, immunohistochemical and gene expression evaluation. Blood was collected for the determination of several serum proliferative and inflammatory markers. Lipid peroxidation, through serum malondialdehyde (MDA) content, and total antioxidant status (TAS) were also evaluated. RESULTS: Sirolimus caused a marked inhibition of bladder tumour growth. When compared with group 3, group 4 had a reduced proportion of rats with tumour (three of eight vs eight of 12), and significantly fewer tumours per rat, with a mean (sd) of 1.00 (0.0) vs 1.88 (0.35), and tumour volume per tumour, of 0.30 (0.11) vs 66.1 (48.9) mm³, with less aggressive histological changes, i.e. a marked reduction in hyperplasia (four of eight vs 12/12), high-grade dysplasia (four of eight vs 11/12) and urothelial tumour. Rats in group 4 had no infiltrative bladder cancers and had a lower incidence of high-grade tumours than rats in group 3. The rats in group 4 had decreased serum levels of transforming growth factor-ß1, higher levels of tumour necrosis factor-α, and higher levels of serum TAS and a better serum MDA/TAS ratio, a marker of more favourable redox status. Furthermore, the down-regulation of bladder caspase 3 gene expression and the increased Ki67 immunostaining in group 3 were significantly attenuated in group 4. CONCLUSIONS: Sirolimus given as an oral agent, 2 mg/kg/day, significantly inhibited rat bladder carcinogenesis. Sirolimus reduced the number and volume of tumours and induced a less aggressive histological behaviour. This might be due to antiproliferative and antioxidant properties, as well as to the restoration of apoptotic pathways.