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Divergent Effects of Ornithine Decarboxylase Inhibition on Murine Erythropoietic Precursor Cell Proliferation and Differentiation¹

Division of Hematology-Oncology, University of Virginia Department of Internal Medicine, Charlottesville, Virginia 22908 [E. O. N., G. P., S. L., A. T.], and Merrell Dow Research Center, Cincinnati, Ohio 45215 [A. K., P. P. M.]

Following the administration of a selective irreversible inhibitor of ornithine decarboxylase (ODC), DL--difluoromethylornithine (DFMO), proliferation of early erythropoietic precursors was enhanced both in nonanemic and anemic mice. In the bone marrow, the absolute number of precursor cells which give rise to erythroid bursts and colonies in methylcellulose was increased 2- to 4-fold during a 5-day period. This stimulation could be abrogated by administration of putrescine, confirming the association of the stimulatory effect with polyamine biosynthesis most likely by a depression of ODC activity and subsequent depression of the synthesis of putrescine. The stimulatory effect by DFMO in vivo was also reflected by an increase in the number of erythroid colonies in diffusion chambers implanted both in nonanemic and anemic mice and was also eliminated by concomitant administration of putrescine to the host. No change in the absolute number of morphologically recognizable nucleated erythroid cells in the bone marrow, hematocrit, and reticulocyte count in nonanemic mice during the 14 days of DFMO was detected. In an attempt to determine whether the stimulatory in vivo effect was directly on burst-forming and colony-forming units erythroid or whether it was a consequence of efflux from an earlier compartment, we determined the number of these precursors in S phase following DFMO administration and demonstrated increased kill by [³H]-thymidine, suggesting that cell cycle status was modulated via ODC. Results from in vitro culture do not explain observations in in vivo setting because, if inhibition of burst-forming and colony-forming unit erythroid differentiation as judged by low colony yield in methylcellulose had also occurred in vivo, a decrease in the number of erythroid precursors in the bone marrow and peripheral blood reticulocytes would have been expected. Based on these data, we conclude that ODC plays an important role in proliferation, but not differentiation, of erythroid precursor cells in vivo.

¹ Supported by USPHS Grant ROI-AM27423-01A2, American Cancer Society Grant CH242, and a grant from Horsley Cancer Foundation.

Received 4/19/82. Accepted 1/ 5/83.

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