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Effects of N⁴-Behenoyl-1-ß-D-Arabinofuranosylcytosine on Blast Progenitors of Acute Myeloblastic Leukemia¹

Departments of Laboratory Medicine [N. N.] and Internal Medicine 1 [S. T., T. S., K. N., Y. Y., Y. I.], Tokyo Medical and Dental University, Yushima I-5-45, Bunkyo-Ku, Tokyo 113; Tokyo Metropolitan Komagome Hospital, Honkomagome 3-18-22, Bunkyo-Ku, Tokyo 113 [Y. M.]; and Tokyo Metropolitan Bokuto Hospital, Koutoubashi 4-23-15, Sumida-Ku, Tokyo 130 [J. T.], Japan

To determine the antileukemic effect of N⁴-behenoyl-1-ß-D-arabinofuranosylcytosine (BH-AC), a synthetic masked compound of 1-ß-D-arabinofuranosylcytosine, the pharmacokinetics and suppressive effect on leukemic blast progenitors of BH-AC were studied. When BH-AC was added to the suspension culture of leukemic cells, BH-AC gradually decreased in concentration in the culture media and was rapidly taken into the cellular fraction. The conversion from BH-AC to 1-ß-D-arabinofuranosylcytosine was noted in both the culture media and the cellular fraction. The concentration of 1-ß-D-arabinofuranosylcytosine converted from BH-AC in the culture medium gradually increased during 7 days of culture, although the rate of conversion was variable among the samples.

BH-AC suppressed primary and secondary blast colony formation in a dose responsive manner. BH-AC also suppressed the recovery of clonogenic cells in suspension culture. The suppression by BH-AC was more prominent in secondary blast colony formation and the recovery of clonogenic cells in suspension culture than in primary blast colony formation. Secondary blast colony formation and the recovery of clonogenic cells in suspension are considered to reflect the self-renewal of blast progenitors, while primary blast colony formation is considered to reflect the terminal divisions of blast progenitors. The results obtained in the present study suggest that BH-AC is more effective to suppress the self-renewal of blast progenitors than the terminal divisions. The findings offer a theoretical basis in the utility of BH-AC in the therapy of acute myeloblastic leukemia.

¹ Supported in part by a Grant-in-aid for Scientific Research from the Ministry of Education, Science and Culture, Japan.

² To whom requests for reprints should be addressed.

Received 6/25/90. Accepted 9/ 5/90.