Resistance to adriamycin in human chronic promyeloleukemia line K562 correlates with directed genome destabilization--amplification of MDR1 gene and nonrandom changes in karyotype structure.
Three independent subclones (B2, B3 and C9) of human myelogenous leukemia cell line K562 selected with adriamycin (ADM) were analysed. Cross-resistance of these ADM-resistant cells was examined for a resistance to the number of drugs including colchicine, actinomycin D and ethidium bromide. MDR 1 gene amplification in B3 and C9 subclones was detected using Southern-hybridization with specific probe. Additional genetical material was found in genomes of resistant cells by analysis of G-banded metaphase chromosomes. An extraordinarily long marker chromosome was observed in every C9 metaphase plate. The character of this chromosome G-banding suggests that it may be a derivative of chromosome 5 containing a large homogeneously staining region (HSR) in locus 5q15. Both B2 and B3 subclones expressed double minute chromosomes (DMs) in 5% of cells. In the course of a prolonged cultivation (about 2 years) of C9 cells in the presence of ADM a progressive karyotype destabilization was observed: the frequency of new markers formation in C9 cells increased, cells having additional copies of marker chromosome with HSR appeared, the length of HSR varied, coexistence of HSR and DMs being found in several C9 cells. These karyotypical changes may be regarded as patterns of genome destabilization due to the multidrug resistance of K562/ADM cells.
Grinchuk
T M
TM
Institute of Cytology, Russian Academy of Sciences, St. Petersburg.
Pavlenko
M A
MA
Lipskaia
L A
LA
Sorokina
E A
EA
Tarunina
M V
MV
Berezkina
E V
EV
Kovaleva
Z V
ZV
Ignatova
T N
TN
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002895:Chromosomes, Human, Pair 5; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005784:Gene Amplification; D019450:Genes, MDR; D005819:Genetic Markers; D006801:Humans; D020014:K562 Cells; D007621:Karyotyping
D000970:Antineoplastic Agents; D005819:Genetic Markers; D004317:Doxorubicin