title: Evaluation of drugs for elimination of leukemic cells from the bone marrow of patients with acute leukemia.
abstract: 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.
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001215:Asparaginase / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects* / Q000473:pathology; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D005047:Etoposide / Q000494:pharmacology; D006854:Hydrocortisone / Q000494:pharmacology; D007945:Leukemia, Lymphoid / Q000473:pathology*; D009942:Organometallic Compounds / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D014750:Vincristine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D013141:Spiro Compounds; D001761:Bleomycin; C026818:spirogermanium; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D001215:Asparaginase; C011272:perfosfamide; D006854:Hydrocortisone