Targeting of neoglycoprotein-drug conjugates to cultured human embryonal carcinoma cells.
Fluorescent neoglycoproteins were used to screen for the presence and sugar specificities of cell surface lectins in two human embryonal carcinoma cell lines. Efficient labeling correlated with extent of lectin-mediated uptake of neoglycoproteins, as measured by inhibition of DNA synthesis by drug-neoglycoprotein conjugates. These conjugates contain covalently linked carbohydrate moieties on the carriers to render them accessible to the membrane lectins, most effectively galactosides and alpha-glucosides. They furthermore contain chemically linked cytotoxic drugs (etoposide, cis-diamminedichloroplatinum II and methotrexate) which are intracellularly released after lysosomal breakdown of the carrier, as indicated by the effect of leupeptin. Sugars can confer a greater than 10-fold increase in cytotoxic capacity to the nonglycosylated carrier-drug conjugate, nearly reaching the level of toxicity of the freely diffusible drug. Two different neoglycoproteins, reacting with independently targeted membrane lectins, were shown to be useful in a model for combination chemotherapy. These results therefore suggest potential usefulness of custom-made glycosylated carriers in the targeting of therapeutic agents to human embryonal carcinoma cells.
D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D006023:Glycoproteins / Q000627:therapeutic use*; D006801:Humans; D037102:Lectins; D007976:Leupeptins / Q000494:pharmacology; D008727:Methotrexate / Q000008:administration & dosage; D014677:Pharmaceutical Vehicles; D011956:Receptors, Cell Surface / Q000502:physiology; D013724:Teratoma / Q000188:drug therapy*
D000970:Antineoplastic Agents; D006023:Glycoproteins; D037102:Lectins; D007976:Leupeptins; D014677:Pharmaceutical Vehicles; D011956:Receptors, Cell Surface; D005047:Etoposide; C032854:leupeptin; D002945:Cisplatin; D008727:Methotrexate