Development and characterization of a human myelogenous leukemia cell line resistant to 4'-(9-acridinylamino)-3-methanesulfon-m-anisidide.
The human myelogenous leukemia cell line HL-60 was made resistant to amsacrine (m-AMSA) by repeated exposure in vitro to increasingly large doses of the drug. Resistance to m-AMSA developed in a triphasic process and was accompanied by a slightly slower growth rate and cloning efficiency and a more differentiated morphological phenotype. Extensive chromosomal rearrangement also took place. Among other chromosomal aberrations, one of the No. 6 homologues showed an added segment on the long arm in the form of an homogeneously staining region. One of the homologues of chromosome 14 in every cell showed a deletion of the distal end of the long arm that was replaced by an unidentified homogeneously staining segment. Membrane-associated 170 kd glycoprotein was not overexpressed in the resistant cells, which together with an absence of cross-resistance to Vinca alkaloids and anthracyclines points toward a mechanism of resistance different from multidrug resistance. The ability of resistant cells to respond to differentiation-inducing agents was not significantly changed as compared with that of the parental line. Growth of resistant cells in the absence of m-AMSA for over 200 population doublings within a period of more than 1.5 years did not result in reversion of the resistance, suggesting a stable genomic change. Resistance was not due to a decrease in the bioavailability of the drug. Uptake of [14C]m-AMSA by either whole cells or isolated nuclei of resistant cells exceeded that of the parental cell line, and outward transport of the drug was not more active; thus there were higher levels of intracellularly bound drug. The cell line represents an excellent model for studies of the mechanisms of resistance to m-AMSA and its modulation in human myelogenous leukemia.
Beran
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M
Andersson
B S
BS
D000677:Amsacrine / Q000378:metabolism / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004317:Doxorubicin / Q000633:toxicity; D004351:Drug Resistance; D007621:Karyotyping; D007700:Kinetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology*; D014410:Tumor Stem Cell Assay; D014747:Vinblastine / Q000633:toxicity
D000677:Amsacrine; D014747:Vinblastine; D004317:Doxorubicin