Human megakaryocytic tumor cell lines CHRF-288-11 and HEL (human erythroleukemia) were incubated with antisense phosphodiester (PDE) and phosphorothioate (PS) oligodeoxynucleotides directed against the first six codons of the human serglycin proteoglycan gene. As controls, PDE scrambled and PS sense and scrambled sequences and a probe antisense to a 3′ portion of the coding sequence were used. Treatment with PDE-ODNs did not alter the core protein content of cell or culture medium proteoglycans. Treatment with all the PS-ODNs resulted in loss of the 31 kD) serglycin core protein in the medium, but not the cell-associated proteoglycans, and concomitant appearance of a heavily labeled core protein band at the dye front. This band appears to arise from truncation of the core protein, which leaves the glycosaminoglycan attachment region intact. The higher molecular weight core proteins, which appear to be derived from a betaglycan-like proteoglycan, were not affected by the PDE or PS-ODN treatment. The same effect was seen with or without electroporation, which was used to enhance uptake of the ODNs. Thus treatment of megakaryocytic tumor cells with PS-ODNs appeared to cause a selective degradation of the serglycin core protein in a sequence-independent manner. Degradation most likely occurred intracellularly, because culture supernatants did not degrade exogenously added serglycin proteoglycan, and the presence of superoxide dismutase and catalase in the culture medium during exposure of the cells to the PS-ODNs did not prevent the degradatio