title: 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.
abstract: Aqueous extracts from leaves of the European mistletoe (Viscum album L.) are postulated to exert an anticancer efficacy by cytotoxic and/or immunological mechanisms of action. Although popular as an unconventional therapy modality, no controlled randomized clinical trials are available, reliably documenting a clinically beneficial antineoplastic potential of the various commercial mistletoe preparations. Since previous investigations have focused on the purified galactoside-specific lectin (Viscum album L. agglutinin, VAA) as major biological response modifier in the low-dose range, the objective 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 each) to obtain low-grade and low-stage transitional cell carcinomas. From the onset of the experiment VAA was injected subcutaneously twice a week (1 ng/kg body weight) continuously for either 6 or 15 months. Following an experimental period of 6 months the incidence of bladder carcinomas was 10.2% in rats given exclusively BBN and 6.7% in those additionally treated with VAA. After an experimental time of 15 months 25.8% of the rats fed BBN only and 19.7% of the animals additionally receiving VAA had developed urothelial carcinomas. The differences of the tumor incidences did not reach the level 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 maximum diameter: 3.31 mm) than in those without lectin treatment (mean maximum diameter: 1.88 mm). Quantitative immunocytochemistry analyzing a panel of immune cells yielded no evidence for the ability of the lectin to provoke a substantial, biologically relevant local cellular immune response in the wall of tumor-free and tumor-bearing bladders. From the current experiment it is obvious that galactoside-specific mistletoe lectin failed to protect against, inhibit, delay or reduce development of chemically induced urothelial carcinomas of the urinary bladder even after long-term administration in the clinically recommended schedule. It seems highly unlikely that adjuvant treatment with mistletoe extracts or VAA might favorably influence bladder cancer in patients by immunological effector mechanisms.
authors.affiliation: Center of Pathology, Faculty of Medicine, Georg-August-University, Göttingen, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Kunze
authors.forename: H
authors.initials: H
authors.lastname: Schulz
authors.forename: M
authors.initials: M
authors.lastname: Adamek
authors.forename: H J
authors.initials: HJ
authors.lastname: Gabius
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002085:Butylhydroxybutylnitrosamine; D002295:Carcinoma, Transitional Cell / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D005697:Galactosides / Q000378:metabolism*; D007111:Immunity, Cellular / Q000187:drug effects; D007150:Immunohistochemistry; D015994:Incidence; D037102:Lectins / Q000627:therapeutic use; D014784:Mistletoe / Q000627:therapeutic use; D008517:Phytotherapy; D037121:Plant Lectins; D028321:Plant Preparations; D010940:Plant Proteins; D010946:Plants, Medicinal; D051381:Rats; D017208:Rats, Wistar; D054790:Ribosome Inactivating Proteins, Type 2; D013047:Specific Pathogen-Free Organisms; D014118:Toxins, Biological / Q000008:administration & dosage / Q000627:therapeutic use*; D017211:Treatment Failure; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control*
chemical_list: D016588:Anticarcinogenic Agents; D005697:Galactosides; D037102:Lectins; D037121:Plant Lectins; D028321:Plant Preparations; D010940:Plant Proteins; D054790:Ribosome Inactivating Proteins, Type 2; D014118:Toxins, Biological; C009674:ribosome inactivating protein, Viscum; D002085:Butylhydroxybutylnitrosamine