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Effect of Homoharringtonine on Proliferation and Differentiation of Human Leukemic Cells in Vitro

Department of Medicine, Division of Hematology/Oncology, UCLA Medical Center, Los Angeles, California 90024 [J-Y. Z., D-L. C., H. P. K.], and Department of Medicine, Second Affiliated Hospital of Hunan Medical College, Changsha, People's Republic of China [Z-S. S.]

Homoharringtonine (HHT) is a cephalotaxine ester derived from an evergreen tree of southern China. We studied the effect of HHT on the clonal proliferation and differentiation of human leukemic cells from cell lines and patients. Dose-response studies found that HHT inhibited colony formation of myeloid cell lines (50% inhibitory dose range, 7 to 12 ng/ml), lymphocytic cell lines (50% inhibitory dose range, 4 to 7 ng/ml), and fresh leukemic cells (50% inhibitory dose range, 2 to 25 ng/ml). Pulse-exposure studies showed that colony formation of HL-60 cells was inhibited 50% by HHT (10 to 20 ng/ml) at 45 h and completely inhibited at 72 h. Radioactive precursor studies using HL-60 cells showed that HHT predominantly inhibited protein synthesis as compared with RNA and DNA synthesis. Taking advantage of this, we have found that the combination of HHT with 1-ß-D-arabinofuranosylcytosine (inhibitor of DNA synthesis) was synergistic in the inhibition of HL-60 clonal growth. HHT (2 to 20 ng/ml) also was found to induce up to 28% of HL-60 cells to differentiate toward macrophage-like cells.

¹ To whom requests for reprints should be addressed, at UCLA School of Medicine, Division of Hematology/Oncology, Factor Bldg. 11-240, Los Angeles, CA 90024.

² Supported in part by USPHS Grants CA 26038, CA 32737, CA 33936, and CA 30512 and by the 4E Leukemia Fund in memory of Marilyn Levine, Irvin Epstein, Harold Bass, and Goldie Berman and in honor of Roselle Lewis. Dr. Koeffler is a member of the Jonsson Comprehensive Cancer Center and has a Career Development Award from the NIH.

Received 5/ 8/89. Revised 11/20/89.