Decreased nuclear matrix DNA topoisomerase II in human leukemia cells resistant to VM-26 and m-AMSA

Journal Article · Tue May 01 00:00:00 EDT 1990 · Biochemistry; (USA)

DOI:https://doi.org/10.1021/bi00469a028· OSTI ID:6325325

Fernandes, D J ^[1]; Danks, M K; Beck, W T ^[2]

---

1. Bowman Gray School of Medicine of Wake Forest Univ., Winston-Salem, NC (USA)
2. St. Jude's Children's Research Hospital, Memphis, TN (USA)

CEM leukemia cells selected for resistance to VM-26 (CEM/VM-1) are cross-resistant to various other DNA topoisomerase II inhibitors but not to Vinca alkaloids. Since DNA topoisomerase II is a major protein of the nuclear matrix, the authors asked if alterations in nuclear matrix topoisomerase II might be important in this form of multidrug resistance. Pretreatment of drug-sensitive CEM cells for 2 h with either 5 {mu}M VM-26 or 3 {mu}M m-AMSA reduced the specific activity of newly replicated DNA on the nuclear matrix by 75 and 50%, respectively, relative to that of the bulk DNA. The decatenating and unknotting activities of DNA topoisomerase II were 6- and 7-fold lower, respectively, in the nuclear matrix preparations from the CEM/VM-1 cells compared to parental CEM cells. Western blot analysis revealed that the amount of immunoreactive topoisomerase II in the nuclear matrices of the CEM/VM-1 cells decreased 3.2-fold relative to that in CEM cells. Increasing the NaCl concentration used in the matrix isolation procedure from 0.2 to 1.8 M resulted in a progressive decrease in the specific activity of topoisomerase II in matrices of CEM/VM-1 but not CEM cells, which suggested that the association of the enzyme with the matrix is altered in the resistant cells. These data support the hypothesis that resistance to VM-26 and m-AMSA is directly related to the decreased activity of nuclear matrix topoisomerase II. In CEM/VM-1 cells the interaction of either VM-26 or m-AMSA with nuclear matrix topoisomerase II is specifically diminished.

• OSTI ID: 6325325
• Journal Information: Biochemistry; (USA), Vol. 29:17; ISSN 0006-2960
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
ENZYME INHIBITORS
BIOLOGICAL EFFECTS
ISOMERASES
INHIBITION
TUMOR CELLS
ENZYME ACTIVITY
ALKALOIDS
CELL PROLIFERATION
DNA
SODIUM CHLORIDES
THYMIDINE
TRITIUM COMPOUNDS
TRYPANOSOMES
ALKALI METAL COMPOUNDS
ANIMAL CELLS
AZINES
CHLORIDES
CHLORINE COMPOUNDS
ENZYMES
HALIDES
HALOGEN COMPOUNDS
HETEROCYCLIC COMPOUNDS
HYDROGEN COMPOUNDS
NUCLEIC ACIDS
NUCLEOSIDES
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PYRIMIDINES
RIBOSIDES
SODIUM COMPOUNDS
550201* - Biochemistry- Tracer Techniques