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Annals of Oncology 8:S25-S30, 1997
© 1997 European Society for Medical Oncology

Effects of phosphodiester and phosphorothioate antisense oligodeoxynucleotides on cell lines which overexpress c-myc: Implications for the treatment of Burkitt's lymphoma

S. A. Williams, E. R. Gillan, E. Knoppel, J. S. Buzby, Y. Suen and M. S. Cairo

Division of Hematology/Oncology and Blood and Bone Marrow Transplantation, Children's Hospital of Orange County Orange, CA, USA

The product of the c-myc proto-oncogene is a highly conserved nuclear phosphoprotein whose expression is closely linked to cellular proliferation and differentiation. We have been interested in developing an antisense oligodeoxynucleotide (ODN) strategy to inhibit the proliferation of c-myc-dependent malignancies for use in future specific therapies andbone marrow purging regimens. Our experimental approach was to incubate either antisense or sense ODNs, spanning the 5' cap region of the c-myc gene, with c-myc overexpressing cell lines (HL-60, Raji, MJBL, CA-46) for up to seven days. Proliferation assay to test the inhibitory effect of an unmodified antisense ODN 15- mer (GCACAGCTCGGGGGT) showed that concentrations as low as 50 µg/ml significantly decreased proliferation of HL-60cells by approximately 40% (P < 0.0001; n = 6) compared to controls. Clonogenic assays showed that the same antisense ODN inhibited colony formationby MJBL (40%) and Raji (52%) cells. Subsequent experiments to study the effect of a more nuclease-stable, phosphorothioate-modified antisense ODN 18-mer (GCAGCACAGCTCGGGGGT) revealed66% inhibition of HL-60 cell proliferation at 96 and 120 hours at 50 µg/ml, whereas sense ODN control had no effect. However, tenfold less of the modified antisense ODN (1 µg/mi) was required to inhibit proliferation of HL-60 cells by 50% compared to the unmodified antisense ODN. A decrease in the HL- 60 native c-myc protein level was also observed with 100 µg/ml of modified antisense ODN, but not with the sense ODN control, by immunoblot analysis. Additionally, concentrations up to 10 µg/ml of either modified antisense or sense ODN did not decrease CFU-GM formation (145 ± 35%, P = 0.27) in human bone marrow, suggesting that these levels of ODN would have a negligible effecton normal hematopoietic cells. These pilot data suggest that modified antisense ODN directed at the cap region of the c-myc gene could specifically inhibit c-myc expression at a single, lower dose than unmodified ODN and may play a future role in inhibiting the growth of c-myc-dependent malignant cells.

antisense, Burkitt's lymphoma, HL-60, phosphorothioate, Raji


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