DEVELOPMENT AND CHARACTERIZATION OF A HUMAN MYELOGENOUS LEUKEMIA-CELL LINE RESISTANT TO 4'-(9-ACRIDINYLAMINO)-3-METHANESULFON-META-ANISIDIDE

  • 1 April 1987
    • journal article
    • research article
    • Vol. 47  (7) , 1897-1904
Abstract
The human myelogenous leukemia cell line HL-60 was made resistant to amsarcrine (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 the 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 overexposed 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 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 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.