Suitability of a new stable acetal analogue of aldoifosphamide for purging leukemic cells from human bone marrow.
The in vitro cytotoxic properties of acetaldoifosphamide, a new chemically stable bis-acetate analogue of aldoifosphamide that requires enzymatic activation by cellular carboxylate esterases, has been compared with that of 4-hydroperoxycyclophosphamide (4-HC). On a molar basis, acetaldoifosphamide was 8-10 times more potent than 4-HC against two different human leukemic myeloid cell lines, but only twice as potent as 4-HC against normal bone marrow granulocyte-macrophage colony-forming cells (GM-CFC). Acetaldoifosphamide retained its activity against leukemic cell lines that were highly resistant to the antileukemic drugs doxorubicin and m-AMSA. GM-CFC doubling times after exposure of bone marrow to high concentrations of acetaldoifosphamide in suspension cultures were 6-12 hours. Similar doubling times were obtained after incubation of marrow with 4-HC. Acetaldoifosphamide has a sparing effect on hematopoietic stem cells that is similar to that found for 4-HC; however, it is considerably more potent than 4-HC. Acetaldoifosphamide is different from 4-HC in its chemical stability and its unique requirement for carboxylate esterase activation. We conclude that acetaldoifosphamide may have advantages over 4-HC for in vitro purging of leukemic cells from human bone marrow.
Andersson
B S
BS
Department of Hematology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Wang
Y Q
YQ
McCredie
K B
KB
Farquhar
D
D
D000970:Antineoplastic Agents; D001853:Bone Marrow / Q000187:drug effects* / Q000473:pathology; D001854:Bone Marrow Cells; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007069:Ifosfamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000473:pathology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology
D000970:Antineoplastic Agents; C064634:acetaldoifosphamide; D003520:Cyclophosphamide; C011272:perfosfamide; D007069:Ifosfamide