The
disaccharide moiety is responsible for the
tumor cell targeting properties of
bleomycin (BLM). While the aglycon (
deglycobleomycin) mediates DNA cleavage in much the same fashion as
bleomycin, it exhibits diminished cytotoxicity in comparison to BLM. These findings suggested that BLM might be modular in nature, composed of
tumor-seeking and tumoricidal domains. To explore this possibility, BLM analogues were prepared in which the
disaccharide moiety was attached to
deglycobleomycin at novel positions, namely, via the
threonine moiety or C-terminal substituent. The analogues were compared with BLM and deglycoBLM for DNA cleavage,
cancer cell uptake, and cytotoxic activity. BLM is more potent than deglycoBLM in supercoiled plasmid
DNA relaxation, while the analogue having the
disaccharide on
threonine was less active than deglycoBLM and the analogue containing the C-terminal
disaccharide was slightly more potent. While having unexceptional DNA cleavage potencies, both glycosylated analogues were more cytotoxic to cultured DU145
prostate cancer cells than deglycoBLM.
Dye-labeled conjugates of the cytotoxic BLM aglycons were used in imaging experiments to determine the extent of cell uptake. The rank order of internalization efficiencies was the same as their order of cytotoxicities toward DU145 cells. These findings establish a role for the BLM
disaccharide in
tumor targeting/uptake and suggest that the
disaccharide moiety may be capable of delivering other
cytotoxins to
cancer cells. While the mechanism responsible for uptake of the BLM
disaccharide selectively by
tumor cells has not yet been established, data are presented which suggest that the metabolic shift to glycolysis in
cancer cells may provide the vehicle for selective internalization.