Resistance of Mammalian Tumor Cells to Inhibitors of DNA Topoisomerase II

Beck, William T.; Danks, Mary K.; Wolverton, Judith S.; Chen, M; Granzen, Bernd; Kim, R; Suttle, D P

doi:10.1016/s1054-3589(08)61136-9

Cited by 43 publications

(24 citation statements)

References 55 publications

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“…In a recent review, several Topoll drug-resistant cell lines were listed (Beck et al, 1994b). The Topoll-related resistance mechanisms, which were also reviewed, were almost always found to involve the Topolloc isoenzyme.…”

Section: Discussionmentioning

confidence: 99%

“…Less cleavable complex formation can be due to a decrease in TopoIl protein, Topoll point mutations changing drug or ATP binding or the binding characteristics of Topoll to DNA, changed cellular localisation of Topoll (Feldhoff et al, 1994) or an altered phosphorylation status of the enzyme (reviewed in Beck et al, 1994b;Pommier et al, 1994). Previously, we have described a cell line panel derived from the small-cell lung carcinoma (SCLC) cell line GLC4, with increasing doxorubicin resistance (Versantvoort et al, 1995).…”

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confidence: 99%

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Differential expression of DNA topoisomerase II α and -β in P-gp and MRP-negative VM26, mAMSA and mitoxantrone-resistant sublines of the human SCLC cell line GLC4

Withoff

Vries²,

Keith³

et al. 1996

Br J Cancer

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Summary Sublines of the human small-cell lung carcinoma (SCLC) cell line GLC4 with acquired resistance to teniposide, amsacrine and mitoxantrone (GLC4/VM20 ,, GLC4/AM3, and GLC4/MIT60 ,, respectively) were derived to study the contribution of DNA topoisomerase Ila and -,B (Topolla and -,B) to resistance for Topolltargeting drugs. The cell lines did not overexpress P-glycoprotein or the multidrug resistance-associated protein but were cross-resistant to other TopoIl drugs. GLC4/VM20x showed a major decrease in Topolla protein (54%; for all assays presented in this paper the GLC4 level was defined to be 100%) without reduction in TopoII,B protein; GLC4/AM3X showed only a major decrease in TopoII,B protein (to 18%) and not in Topolla.In GLC4/MIT60 ,, the Topolla and -,B protein levels were both decreased (Topolla to 31%; TopoII,B protein was undetectable). The decrease in Topolla protein in GLC4/VM20 and GLC4/MIT60,,, was mediated by decreased Topollcx mRNA levels. Loss of Topolla gene copies contributed to the mRNA decrease in these cell lines. Only in the GLC4/MIT60x cell line was an accumulation defect observed for the drug against which the cell line was made resistant. In conclusion, Topollcx and -/3 levels were decreased differentially in the resistant cell lines, suggesting that resistance to these drugs may be mediated by a decrease in a specific isozyme.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Differential expression of DNA topoisomerase II α and -β in P-gp and MRP-negative VM26, mAMSA and mitoxantrone-resistant sublines of the human SCLC cell line GLC4

Withoff

Vries²,

Keith³

et al. 1996

Br J Cancer

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“…Religation is influenced less by the base sequence on the opposite strand. DISCUSSION A number of factors contribute to the sensitivity of cells toward agents targeted to the type II topoisomerases (32)(33)(34)(35). Top2 mutations that alter drug-induced DNA cleavage result in marked alterations, ranging from high resistance (26,36,37) to severalfold hypersensitivity (19,26).…”

Section: Reversibility Of the Etoposide-induced Cleavage Complexesmentioning

confidence: 99%

Mutation of a Conserved Serine Residue in a Quinolone-resistant Type II Topoisomerase Alters the Enzyme-DNA and Drug Interactions

Strumberg

Nitiss²,

Rose³

et al. 1999

Journal of Biological Chemistry

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A Ser740 3 Trp mutation in yeast topoisomerase II (top2) and of the equivalent Ser 83 in gyrase results in resistance to quinolones and confers hypersensitivity to etoposide (VP-16). We characterized the cleavage complexes induced by the top2 S740W in the human c-myc gene. In addition to resistance to the fluoroquinolone CP-115,953, top2 S740W induced novel DNA cleavage sites in the presence of VP-16, azatoxin, amsacrine, and mitoxantrone. Analysis of the VP-16 sites indicated that the changes in the cleavage pattern were reflected by alterations in base preference. C at position ؊2 and G at position ؉6 were observed for the top2 S740W in addition to the previously reported C؊1 and G؉5 for the wildtype top2. The VP-16-induced top2 S740W cleavage complexes were also more stable. The most stable sites had strong preference for C؊1, whereas the most reversible sites showed no base preference at positions ؊1 or ؊2. Different patterns of DNA cleavage were also observed in the absence of drug and in the presence of calcium. These results indicate that the Ser 740 3 Trp mutation alters the DNA recognition of top2, enhances its DNA binding, and markedly affects its interactions with inhibitors. Thus, residue 740 of top2 appears critical for both DNA and drug interactions.DNA topoisomerases are enzymes that catalyze changes in the topology of DNA via a mechanism involving the transient breakage and rejoining of phosphodiester bonds in the DNA backbone (1). Studies in both prokaryotic and eukaryotic cells have demonstrated the importance of topoisomerases in transcription, DNA replication, and chromosome segregation. The type II topoisomerases, which make transient double-strand breaks and change the linking number of DNA in steps of two, play key roles in chromosome structure. In eukaryotic cells, these enzymes are essential for chromosome condensation/decondensation and decatenation of chromosome loops during mitosis (2, 3).Topoisomerase II (top2) 1 has also been identified as a major target of chemotherapeutic agents that are specifically active against prokaryotic (4) or cancer cells (5-8). Fluoroquinolones are antibacterial agents that target DNA gyrase (the prokaryotic type II topoisomerase) (9), whereas a variety of DNAintercalating agents such as anthracyclines, amsacrine, and mitoxantrone and nonintercalating agents such as the epipodophyllotoxin etoposide (VP-16) are active against eukaryotic top2 and are clinically important anti-cancer agents (5-8).Azatoxin is also a nonintercalative top2 poison (10).Recently, it has been shown that 6,8-difluoro-7-(4Ј-hydroxyphenyl)-1-cyclopropyl-4-quinolone-3-carboxylic acid (CP-115, 953), a fluoroquinolone closely related to ciprofloxacin, is highly toxic to mammalian cells in culture (11,12). Studies in yeast demonstrated that top2 is the primary physiological target for this quinolone (13). Unlike etoposide, which stabilizes top2-mediated DNA cleavage primarily by inhibiting the religation reaction of top2, CP-115,953 stabilizes DNA cleavage by enhancing the forward rate o...

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“…Concerning topoisomerase (topo) inhibitors, reduced or mutated topo I or II has been found to confer drug resistance to the respective agents. 1,2) Decreased retention of drugs related to multidrug resistance or multidrug resistance protein also renders the cells resistant. [1][2][3][4] Apoptosisresistant cells demonstrate other mechanisms of resistance.…”

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confidence: 99%

“…1,2) Decreased retention of drugs related to multidrug resistance or multidrug resistance protein also renders the cells resistant. [1][2][3][4] Apoptosisresistant cells demonstrate other mechanisms of resistance. 5) These mutants do not display alterations in either the activity or quantity of topo II, with similar rates of drug efflux being seen in both apoptosis-sensitive and -resistant cell types.…”

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confidence: 99%

Different Susceptibilities of Postmitotic Checkpoint‐proficient and ‐deficient Balb/3T3 Cells to ICRF‐193, a Catalytic Inhibitor of DNA Topoisomerase II

Nishida

Seto

Ishida

2001

Japanese Journal of Cancer Research

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Resistance of Mammalian Tumor Cells to Inhibitors of DNA Topoisomerase II

Cited by 43 publications

References 55 publications

Differential expression of DNA topoisomerase II α and -β in P-gp and MRP-negative VM26, mAMSA and mitoxantrone-resistant sublines of the human SCLC cell line GLC4

Differential expression of DNA topoisomerase II α and -β in P-gp and MRP-negative VM26, mAMSA and mitoxantrone-resistant sublines of the human SCLC cell line GLC4

Mutation of a Conserved Serine Residue in a Quinolone-resistant Type II Topoisomerase Alters the Enzyme-DNA and Drug Interactions

Different Susceptibilities of Postmitotic Checkpoint‐proficient and ‐deficient Balb/3T3 Cells to ICRF‐193, a Catalytic Inhibitor of DNA Topoisomerase II

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