[3H]Harringtonine was shown to be taken up rapidly by L1210/0 cells using a fast-mixing, fast-separating technique and was retained with a slow rate of limited release to the medium. Cells resistant to vincristine (L1210/VCR) showed impaired capability to take up the drug at 20°. Its initial uptake in L1210 sublines in vitro was: L1210/0 > L1210/cyclophosphamide, L1210/1-β-d-arabinofuranosylcytosine, L1210/6-mercaptopurine > L1210/5-fluorouracil, L1210/Adriamycin > L1210/VCR. In [3H]harringtonine-preloaded cells, L1210/0 retained significantly more radioactivity than did L1210/VCR cells after repeated washing with fresh medium at 37°. The radioactivity appeared to be predominantly bound to the microsomal fractions. [3H]Leucine incorporation into protein in L1210/0 cells was inhibited 90% within 15 min by harringtonine (0.5 µg/ml); incorporation of [3H]thymidine into DNA and [3H]cytidine into RNA was much less inhibited and showed an apparent lag of onset for 5 and 10 min, respectively. The relative potency of harringtonine to inhibit [3H]leucine incorporation in the above sublines in vitro follows an order similar to their rates of uptake of harringtonine by these sublines of cells. The efficacy of harringtonine, 2.4 or 3.6 mg/kg i.p., in increasing the life span of C57BL/6 × DBA/2 F1 mice bearing the sublines of leukemic cells, on the average, was: L1210/0 > L1210/cyclophosphamide, L1210/6-mercaptopurine > L1210/1-β-d-arabinofuranosylcytosine, L1210/5-fluorouracil > L1210/Adriamycin, L1210/VCR. These results suggest that: (a) protein synthesis is the major initial target for the effect of harringtonine; (b) harringtonine bound more tightly to the cellular components of VCR-sensitive leukemic cells than to VCR-resistant cells; and (c) cellular uptake of harringtonine and the relative potency of inhibiting protein synthesis in sublines have a rank order similar to the chemotherapeutic efficacy of harringtonine in these cells.

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This study was supported by Grants CA 18856 and CA 27569 from the National Cancer Institute, NIH, USPHS, and from the Elsa U. Pardee Foundation. The preliminary results of this study have been reported (8).

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