Cross-resistance of an amsacrine-resistant human leukemia line to topoisomerase II reactive DNA intercalating agents. Evidence for two topoisomerase II directed drug actions

Journal Article · Tue Apr 23 04:00:00 EDT 1991 · Biochemistry; (United States)

DOI:https://doi.org/10.1021/bi00230a032· OSTI ID:5557941

Zwelling, L A; Mayes, J; Hinds, M; Chan, D; Altschuler, E; Carroll, B; Parker, E; Deisseroth, K; Radcliffe, A; Seligman, M; Li, Li; Farquhar, D ^[1]

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1. Univ. of Texas M.D. Anderson Cancer Center, Houston (USA)

HL-60/AMSA is a human leukemia cell line that is 50-100-fold more resistant than its drug-sensitive HL-60 parent line to the cytotoxic actions of the DNA intercalator amsacrine (m-AMSA). HL-60/AMSA topoisomerase II is also resistant to the inhibitory actions of m-AMSA. HL-60/AMSA cells and topoisomerase II are cross-resistant to anthracycline and ellipticine intercalators but relatively sensitive to the nonintercalating topoisomerase II reactive epipodophyllotoxin etoposide. The authors now demonstrate that HL-60/AMSA and its topoisomerase II are cross-resistant to the DNA intercalators mitoxantrone and amonafide, thus strongly indicating that HL-60/AMSA and its topoisomerase II are resistant to topoisomerase II reactive intercalators but not to nonintercalators. At high concentrations, mitoxantrone and amonafide were also found to inhibit their own, m-AMSA's, and etoposide's abilities to stabilize topoisomerase II-DNA complexes. These results suggest that the cytotoxicity of m-AMSA and etoposide is initiated primarily by the stabilization of the topoisomerase II-DNA complex. Other topoisomerase II reactive drugs may inhibit the enzyme at other steps in the topoisomerization cycle, particularly at elevated concentrations. Under these conditions, these latter drugs may not produce protein-associated DNA cleavage while still inhibiting topoisomerase II function as well as the actions of other topoisomerase II reactive drugs.

• OSTI ID: 5557941
• Journal Information: Biochemistry; (United States), Journal Name: Biochemistry; (United States) Vol. 30:16; ISSN 0006-2960; ISSN BICHA
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ANIMAL CELLS
ANIMALS
ANTINEOPLASTIC DRUGS
AZINES
BIOLOGICAL EFFECTS
CARBON 14 COMPOUNDS
CARBON COMPOUNDS
CELL PROLIFERATION
CHEMICAL REACTIONS
CLATHRATES
CROSS-LINKING
DISEASES
DNA
DOSE-RESPONSE RELATIONSHIPS
DRUGS
ENZYMES
HETEROCYCLIC COMPOUNDS
HYDROGEN COMPOUNDS
IMMUNE SYSTEM DISEASES
ISOMERASES
LABELLED COMPOUNDS
LEUKEMIA
MAMMALS
MAN
NEOPLASMS
NUCLEIC ACIDS
NUCLEOSIDES
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
POLYMERIZATION
PRIMATES
PYRIMIDINES
RIBOSIDES
SENSITIVITY
THYMIDINE
TRITIUM COMPOUNDS
TUMOR CELLS
VERTEBRATES