Long-term administration of galactoside-specific mistletoe lectin in an animal model: no protection against N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in rats and no induction of a relevant local cellular immune response

Aqueous extracts from leaves of the European mistletoe (Viscum album L.) ar e postulated to exert an anticancer efficacy by cytotoxic and/or immunologi cal mechanisms of action. Although popular as an unconventional therapy mod ality, no controlled randomized clinical trials are available, reliably doc umenting a clinically beneficial antineoplastic potential of the various co mmercial mistletoe preparations. Since previous investigations have focused on the purified galactoside-specific lectin (Viscum album L. agglutinin, V AA) as major biological response modifier in the low-dose range, the object ive of the present experimental study was to examine its effect on N-butyl- N-(4-hydroxybutyl)-nitrosamine (BBN)-induced carcinogenesis in the urinary bladder of rats, a suitable animal model for human disease. The carcinogen was fed by gavage in three fractionated low doses (150 mg/kg body weight ea ch) to obtain low-grade and low-stage transitional cell carcinomas. From th e onset of the experiment VAA was injected subcutaneously twice a week (1 n g/kg body weight) continuously for either 6 or 15 months. Following an expe rimental period of 6 months the incidence of bladder carcinomas was 10.2% i n rats given exclusively BBN and 6.7% in those additionally treated with VA A. After an experimental time of 15 months 25.8% of the rats fed BBN only a nd 19.7% of the animals additionally receiving VAA had developed urothelial carcinomas. The differences of the tumor incidences did not reach the leve l of statistical significance, neither after an experimental duration of 6 (P = 0.88) nor of 15 months (P = 0.71). A difference was found in the size of the transitional cell carcinomas. They proved to be significantly larger (P = 0.02) in the rats additionally treated with VAA for 15 months (mean m aximum diameter: 3.31 mm) than in those without lectin treatment (mean maxi mum diameter: 1.88 mm). Quantitative immunocytochemistry analyzing a panel of immune cells yielded no evidence for the ability of the lectin to provok e a substantial, biologically relevant local cellular immune response in th e wall of tumor-free and tumor-bearing bladders. From the current experimen t it is obvious that galactoside-specific mistletoe lectin failed to protec t against, inhibit, delay or reduce development of chemically induced uroth elial carcinomas of the urinary bladder even after long-term administration in the clinically recommended schedule. It seems highly unlikely that adju vant treatment with mistletoe extracts or VAA might favorably influence bla dder cancer in patients by immunological effector mechanisms.