Z G

and later by Samuelsson and co-workers (1959, 1961, 1970). Fractionations of the crude viscotoxins led to the isolation of several homogenous, cytotoxic components termed B, A2, A3 and 1-PS (Samuelsson and Pettersson, 1970), and A1 and U-PS (Schaller et al., 1996) or I, II, III, IVb (Konopa et al., 1980; Woynarowski and Konopa, 1980). The 46 to 50 amino acid polypeptide chains are rich in lysin and arginin, contain six cystein residues at identical positions, and are formed by cleavage of larger precursors (Samuelsson, 1974; Schrader and Apel, 1991). Due to their positive charge, they may form complexes to nucleic acids (Woynarowski and Konopa, 1980).

The cytoxicity of the viscotoxins was assessed mainly by parenteral administration in animals. In cats, intravenous application of viscotoxins at 0.1 mg/kg was lethal for all animals whereas 0.5 mg/kg was lethal for 50% of mice when applied intraperitoneally (Samulesson, 1974). At lower concentrations, application of viscotoxins resulted in hypotension, bradycardia, and negative inotropia of the heart. Thus, an obvious similarity of viscotoxins and cobra cardiotoxins was observed (Rosell and Samuelsson, 1966; Samuelsson, 1974). Few studies have examined the cytotoxicity of viscotoxins to cultured cell lines. Konopa et al. (1980) reported that the isolated polypeptides exhibited cytotoxic activity against the human tumour cell lines KB and HeLa in a concentration range (ED50) of 0.2 to 1.7 ^g/ml. The Yoshida sarcoma cells were more sensitive to the viscotoxins and less sensitive to the ML as compared to the leukaemia cell line Molt-4 (Urech et al., 1995).

Although the primary structure of the viscotoxins share a high degree of similarity, the viscotoxins significantly differ in cytotoxicity (Table 3). Against Yoshida sarcoma cells, the viscotoxins A3 and 1-PS are most effective, followed by A1 and A2, while in lymphocytes A2 and 1-PS were the most effective; the least potent are viscotoxins B and U-PS (Urech et al., 1995, 1996; B├╝ssing et al., 1999c). According to Konopa et al. (1980), the viscotoxins IVa/IVb (A3) and III (A2) were most effective against KB cells whereas viscotoxins I and II (B) were less effective. Qualitative and quantitative differences in the VT pattern of the three European Viscum album subspecies have been described. Viscum album ssp. austriacum lacks viscotoxins A1 and A2, Viscum

Table 3 Cytotoxicity of viscotoxin fractions to cultured cell lines and lymphocytes.

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