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The Effects of Acetaldophosphamide, a Novel Stable Aldophosphamide Analogue, on Normal Human and Leukemic Progenitor Cells in Vitro: Implications for Use in Bone Marrow Purging

DepartmentS of Hematology [M. B., B. S. A., K. B. M.] and Medical Oncology [Y. W., D. F.], Division of Medicine, The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, Houston, Texas 77030

Acetaldophosphamide (A-ALD), a novel in vitro active and stable derivative of aldophosphamide, kills human bone marrow-derived granulocyte-macrophage colony-forming cells (GM-CFC) independent of the cell cycle. The surviving fraction of GM-CFC is an exponential function of the drug concentration and time of exposure. Variation of marrow light-density cell concentration between 2 x 10⁶ and 10 x 10⁶/ml does not significantly influence its GM-CFC toxicity.

Marrow depleted of GM-CFC by A-ALD subsequently generates GM-CFC when grown in suspension cultures. During the early period after treatment with A-ALD the number of surviving GM-CFC (size of surviving GM-CFC compartment) does influence the speed of the GM-CFC repopulation in suspension cultures. The importance of the number of surviving GM-CFCs for the growth and maintenance of GM-CFC population in such suspension cultures diminishes with time. No significant differences are observed after 2 wk, indicating that the ancestor stem cell population and its regenerative potential responsible for in vitro hematopoiesis have not been significantly affected by the drug treatment. A-ALD-treated progenitor cells retain their ability to integrate with the previously established marrow stromal cell layer and generate GM-CFC within this layer to an extent comparable to that of untreated marrow cells.

The effect of A-ALD on human hematopoiesis is comparable to that of 4-hydroperoxycyclophosphamide. Its advantage over 4-hydroperoxy-cyclophosphamide is a greater stability in vitro. It has sparing effect on GM-CFC ancestor cells. Its toxicity to myeloid leukemia cell line (KBM-3)-derived clonogeneic cells is higher than to the GM-CFC. It is similar in doxorubicin-sensitive (KBM-3) and -resistant (KBM-3/DOX) leukemic cells. Thus, A-ALD appears to be a promising drug for in vitro purging of bone marrow cells.

¹ To whom requests for reprints should be addressed, at Department of Hematology, Box 55, The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, 1515 Holcombe Boulevard, Houston, TX 77030.

Received 3/16/87. Revised 10/ 8/87. Accepted 10/14/87.