Evaluation of drugs for elimination of leukemic cells from the bone marrow
of patients with acute leukemia
ML Auber, LJ Horwitz, A Blaauw, S Khorana, S Tucker, T Woods, M Warmuth, KA Dicke, KB McCredie and G Spitzer
Department of Hematology, University of Texas M.D. Anderson Hospital and
Tumor Institute at Houston 77030.
Relatively nonmyelotoxic drugs and drug combinations were investigated for
their ability to eliminate malignant cells from human bone marrow. In vitro
90% inhibitory concentration (IC90) doses were established on granulocyte
macrophage colony-forming units (GM-CFU) in culture of bone marrow by using
the GM-CFU assay for the following drugs: 4- hydroperoxycyclophosphamide
(4-HC), Adriamycin, L-asparaginase, bleomycin, hydrocortisone, VP-16,
spirogermanium, Taxol, and vincristine. The leukemic cell kill efficiency
of these drugs at IC90 doses was compared with that of 4-HC on acute
lymphoid leukemia (ALL) cell lines by using the limiting-dilution assay.
Under these conditions, no single drug was superior to 4-HC. To increase
the in vitro effect in leukemic cell kill, combinations of vincristine with
hydrocortisone, Adriamycin, VP-16, and 4-HC were investigated. Vincristine
at 1 to 5 micrograms/mL increased the marrow cytotoxicity of
hydrocortisone, Adriamycin, and VP-16, but it was protective (subadditive)
with 4-HC. Vincristine and 4-HC in combination was additive to
supraadditive on ALL cell lines, increased the leukemic cell kill by one to
two logs above 4-HC alone at IC90 doses (P less than .05), and was not
affected by the addition of excess marrow cells. The recommended doses for
chemopurging in clinical studies are vincristine, 1 to 5 micrograms/mL,
plus 4-HC, 5 micrograms/mL.
Volume 71,
Issue 1,
pp. 166-172,
01/01/1988
Copyright © 1988 by The American Society of Hematology
