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

Fernandes, Daniel; Danks, Mary K.; Beck, William T.

doi:10.1021/bi00469a028

Cited by 74 publications

(34 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In agreement with our data, a positive correlation was found between mdrl and glutathione-S-transferase mRNA levels in CLL but not the acute leukaemias by Holmes et al (1990b) (Liu, 1989), and similar topoisomerase II activities were found by Holden et al (1990) (Fernandes et al, 1990;DeJong et al, 1990), or the emergence of an altered topoisomerase II enzyme (Pommier et al, 1986) (Madden & Champoux, 1992). Thus, if clinically applicable topoisomerase I specific drugs will be available, their application in those cases eventually could improve chemotherapy.…”

Section: Discussionsupporting

confidence: 91%

“…'Classical' multiple drug resistance (MDR) of cell lines selected in vitro is basically mediated by the P-glycoprotein (for review see Endicott & Ling, 1989). The so-called 'atypical' MDR (at-MDR) where the numerous topoisomerase II inhibitors are affected could be associated with a quantitatively or qualitatively altered activity of topoisomerase II (Pommier et al, 1986;Fernandes et al, 1990;DeJong et al, 1990). Other investigations, however, point to further as yet unrecognised mechanisms or a multifactorial emergence of MDR of in vitro selected cell lines (McGrath & Center, 1988;Deffie et al, 1988;Harker et al, 1989).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Mdr1/P-glycoprotein, topoisomerase, and glutathione-S-transferase π gene expression in primary and relapsed state adult and childhood leukaemias

Gekeler

Frese²,

Noller³

et al. 1992

Br J Cancer

View full text Add to dashboard Cite

Summary In a variety of adult and childhood leukaemia cell samples collected at different states of the disease, we analysed in a series of sequentially performed slot-blot or Northern-blot hybridisation experiments the expression of genes possibly involved in multiple drug resistance (MDR) (mdrl/P-glycoprotein, DNA topoisomerase II, glutathione-S-transferase x), and the expression of the DNA topoisomerase I and histone 3.1 genes. Occasionally, P-glycoprotein gene expression was additionally examined by indirect immunocytofluorescence using the monoclonal antibody C219. No significant difference in mdrl/P-glycoprotein mRNA levels between primary and relapsed state acute lymphocytic leukaemias (ALL) was seen on average. Second or third relapses, however, showed a distinct tendency to an elevated expression of this multidrug transporter gene (up to 10-fold) in part well beyond the value seen in the moderately cross-resistant T-lymphoblastoid CCRF-CEM subline CCRF VCR 100. Increased mdrl/P-glycoprotein mRNA levels were also found in relapsed state acute myelogeneous leukaemias (AML), and in chronic lymphocytic leukaemias (CLL) treated with chlorambucil and/or prednisone for several years. Topoisomerase I and topoisomerase II mRNA levels were found to be very variable. Whereas in all but one case of CLL topoisomerase II mRNA was not detected

show abstract

Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 99%

Mdr1/P-glycoprotein, topoisomerase, and glutathione-S-transferase π gene expression in primary and relapsed state adult and childhood leukaemias

Gekeler

Frese²,

Noller³

et al. 1992

Br J Cancer

View full text Add to dashboard Cite

show abstract

“…The total topo II activity in nuclear extracts could be separated in a free and a DNA-bound portion. 21,22 In order to be active and process DNA, the enzyme must bind to the DNA. 20,23,24 As shown in Table 5, the total topo II activity of KG-1 cells is about 50% of the activity of HL-60 cells.…”

Section: Discussionmentioning

confidence: 99%

Molecular effects of topoisomerase II inhibitors in AML cell lines: correlation of apoptosis with topoisomerase II activity but not with DNA damage

Gieseler¹,

Bauer

Nuessler³

et al. 1999

Leukemia

View full text Add to dashboard Cite

We examined the cellular effects of topo II inhibitors in two human myeloid cell lines, HL-60 and KG-1 cells, with the purpose of finding molecular markers for the sensitivity of leukemia cells to topo II inhibitors. These cell lines are widely used, well characterized and they differ in their sensitivities to topo II inhibitors. Despite the fact that HL-60 cells are p53-negative, they are much more sensitive than KG-1 cells. Three different topo II inhibitors with distinct molecular ways of action have been used. Daunorubicin and aclarubicin are DNA intercalators that secondarily interact with topo II; etoposide, on the other hand, directly binds to the enzyme. In contrast to daunorubicin, which induces protein-associated DNA double-strand breaks due to the blockage of topo II action, aclarubicin inhibits the access of DNA by topo II. No correlation could be established between the drug-induced DNA damage and apoptosis. In fact, the amount and pattern of DNA damage examined with the 'comet assay' was characteristic for each drug in both cell lines. The DNA binding of daunorubicin was slightly higher in HL-60 cells, but there was no notable variance between the cell lines for aclarubicin. The most striking difference could be found for the nuclear topo II activity, which was about half in KG-1 cells and, additionally, less than 1% of the nuclear topo II activity was bound to the DNA in KG-1 cells when compared to HL-60 cells. This fraction of topo II interacts with the inhibitors; subsequently these findings might well explain the variance in the cellular sensitivity. Additional factors are alterations of the apoptotic pathways, eg loss of p53 in HL-60 cells. Although we found no differences in the quantity of DNA damage between the cell lines after drug treatment, the quality of DNA damage appeared to be distinct for each topo II inhibitor. The morphological appearance of the comet tails after treatment was characteristic for each drug. Further studies are necessary to decide whether these in vitro data are compatible with the clinical situation.

show abstract

“…[17][18][19] The resistance of several leukemia cell lines to anthracyclines and epipodophyllotoxins has been associated with a decreased protein expression and/or activity of topoisomerase II enzymes. [20][21][22][23][24][25] In addition, in some particular cell lines, topoisomerase II gene mutations have been identified and suggested to be responsible for the reduced drug sensitivity to DNA topoisomerase inhibitors. [26][27][28][29] Conversely, more recent studies have shown that increasing the intracellular level of the enzyme by transfection of topoisomerase genes can restore the sensitivity of resistant cancer cell lines to DNA topoisomerase inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Modification of topoisomerase genes copy number in newly diagnosed childhood acute lymphoblastic leukemia

et al. 2003

View full text Add to dashboard Cite

Topoisomerase genes were analyzed at both DNA and RNA levels in 25 cases of newly diagnosed childhood acute lymphoblastic leukemia (ALL). The results of molecular analysis were compared to risk group classification of children in order to identify molecular characteristics associated with response to therapy. At diagnosis, allelic imbalance at topoisomerase IIa (TOP2A) gene locus was found in 75% of informative cases whereas topoisomerase I and IIb gene loci are altered in none or only one case, respectively. By semiquantitative Polymerase chain reaction, we found a 2.5 to 8-fold TOP2A gene amplification in 72% of the children, which was correlated to gene overexpression in every case. These results show that TOP2A gene amplification is a frequent event in ALL at diagnosis. Interestingly, we also identified a small population of children that do not present TOP2A gene amplification or gene overexpression and who are significantly associated with very high risk classified patients showing glucocorticoid resistance. In conclusion, characterization of TOP2A gene status in childhood ALL at diagnosis provides useful complementary information for risk assessment.

show abstract

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

Cited by 74 publications

References 29 publications

Mdr1/P-glycoprotein, topoisomerase, and glutathione-S-transferase π gene expression in primary and relapsed state adult and childhood leukaemias

Mdr1/P-glycoprotein, topoisomerase, and glutathione-S-transferase π gene expression in primary and relapsed state adult and childhood leukaemias

Molecular effects of topoisomerase II inhibitors in AML cell lines: correlation of apoptosis with topoisomerase II activity but not with DNA damage

Modification of topoisomerase genes copy number in newly diagnosed childhood acute lymphoblastic leukemia

Contact Info

Product

Resources

About