Novel mechanisms of resistance to inhibitors of DNA topoisomerases

Beck, William T.; Khélifa, Tayeb; Kusumoto, Hiroki; Mo, Yin‐Yuan; Rodgers, Queen E.; Wolverton, Judith S.; Wang, Qinjian

doi:10.1016/s0065-2571(96)00024-6

Cited by 21 publications

(20 citation statements)

References 19 publications

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“…The cell line used for this experiment, CEM/VM-1-5, is 140 times more resistant to the cytotoxic effects of the epipodophyllotoxin teniposide than the parental CEM cell line (17). The resistance of this cell line has been attributed to point mutations involving the genes coding for both topo II␣ and topo II␤, resulting in reduced formation of cleavable complexes, less DNA damage, and less cytotoxicity (6,12,17,21). We treated parental CEM and CEM/VM-1-5 cells with 10 M etoposide or 6 g of cytosine arabinoside per ml for 16 h and assessed the presence of site-specific cleavage by indirect end labeling (Fig.…”

Section: In Vitro Cleavage Of the Mll Bcr By Topo IImentioning

confidence: 99%

DNA Cleavage within the MLL Breakpoint Cluster Region Is a Specific Event Which Occurs as Part of Higher-Order Chromatin Fragmentation during the Initial Stages of Apoptosis

Stanulla

Wang

Chervinsky

et al. 1997

Molecular and Cellular Biology

170

163

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A distinct population of therapy-related acute myeloid leukemia (t-AML) is strongly associated with prior administration of topoisomerase II (topo II) inhibitors. These t-AMLs display distinct cytogenetic alterations, most often disrupting the MLL gene on chromosome 11q23 within a breakpoint cluster region (bcr) of 8.3 kb. We recently identified a unique site within the MLL bcr that is highly susceptible to DNA double-strand cleavage by classic topo II inhibitors (e.g., etoposide and doxorubicin). Here, we report that site-specific cleavage within the MLL bcr can be induced by either catalytic topo II inhibitors, genotoxic chemotherapeutic agents which do not target topo II, or nongenotoxic stimuli of apoptotic cell death, suggesting that this site-specific cleavage is part of a generalized cellular response to an apoptotic stimulus. We also show that site-specific cleavage within the MLL bcr can be linked to the higher-order chromatin fragmentation that occurs during the initial stages of apoptosis, possibly through cleavage of DNA loops at their anchorage sites to the nuclear matrix. In addition, we show that site-specific cleavage is conserved between species, as specific DNA cleavage can also be demonstrated within the murine MLL locus. Lastly, site-specific cleavage during apoptosis can also be identified at the AML1 locus, a locus which is also frequently involved in chromosomal rearrangements present in t-AML patients. In conclusion, these results suggest the potential involvement of higher-order chromatin fragmentation which occurs as a part of a generalized apoptotic response in a mechanism leading to chromosomal translocation of the MLL and AML1 genes and subsequent t-AML.Nonrandom chromosomal aberrations, particularly chromosomal translocations, are frequently found in association with a wide spectrum of malignancies, most prominently leukemias and lymphomas (9,14,47). The available evidence suggests that these nonrandom chromosomal translocations are often causal events leading to malignant transformation (2, 40). However, the molecular mechanisms which cause these translocations remain largely unknown.In many cases, a powerful argument can be made that these translocations are the result of mistakes in normal V(D)J recombinase activity (4, 60). These arguments are based on identification of features that resemble normal V(D)J recombinase activity, such as cryptic heptamer sequences, nontemplated N-region nucleotide addition, and exonucleolytic deletion of germ line nucleotides at the translocation breakpoints (4, 60). Other factors that have been implicated in the generation of nonrandom translocations include homologous recombination events between Alu elements (52) and exposure to DNA-damaging agents (35,36). It has been recognized for some time that DNA-damaging cancer chemotherapeutic agents, such as the topoisomerase II (topo II) inhibitor etoposide (36) and the alkylating agent melphalan (35), can cause chromosomal translocations. For instance, phytohemagglutinin-stimulated peripheral blood ly...

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Section: In Vitro Cleavage Of the Mll Bcr By Topo IImentioning

confidence: 99%

DNA Cleavage within the MLL Breakpoint Cluster Region Is a Specific Event Which Occurs as Part of Higher-Order Chromatin Fragmentation during the Initial Stages of Apoptosis

Stanulla

Wang

Chervinsky

et al. 1997

Molecular and Cellular Biology

170

163

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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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“…Stabilization of this complex by topo II poisons induces DNA damage and cell death (Froelich-Ammon and Osheroff, 1995). Decreased complex formation due to decreased topo II levels is considered to be an important mechanism of tumour-resistance to topo II poisons (Beck and Danks, 1991). The topo II catalytic inhibitor fostriecin is expected to have increased activity against tumour cells with low topo II levels and this was confirmed in in vitro studies (De Jong et al, 1991).…”

mentioning

confidence: 94%

Phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin

Jong

Mulder

Uges³

et al. 1999

Br J Cancer

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SummaryWe conducted a phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin. Fostriecin was administered intravenously over 60 min on days 1-5 at 4-week intervals. Dose was escalated from 2 mg m -2 day -1 to 20 mg m -2 day -1 in 20 patients. Drug pharmacokinetics was analysed with high performance liquid chromatography with UV-detection. Plasma collected during drug administration was tested in vitro for growth inhibition of a teniposide-resistant small-cell lung cancer (SCLC) cell line. The predominant toxicities were elevated liver transaminases (maximum common toxicity criteria (CTC) grade 4) and serum creatinine (maximum CTC grade 2). These showed only a limited increase with increasing doses, often recovered during drug administration and were fully reversible. Duration of elevated alanine-amino transferase (ALT) was dose-limiting in one patient at 20 mg m -2 . Other frequent toxicities were grade 1-2 nausea/vomiting, fever and mild fatigue. Mean fostriecin plasma half-life was 0.36 h (initial; 95% CI, 0-0.76 h) and 1.51 h (terminal; 95% CI, 0.41-2.61 h). A metabolite, most probably dephosphorylated fostriecin, was detected in plasma and urine. No tumour responses were observed, but the plasma concentrations reached in the patients were insufficient to induce significant growth inhibition in vitro. The maximum tolerated dose (MTD) has not been reached, because drug supply was stopped at the 20 mg m -2 dose level. However, further escalation seems possible and is warranted to achieve potentially effective drug levels. Fostriecin has a short plasma half-life and longer duration of infusion should be considered.Keywords: fostriecin; topoisomerase II; phase I; pharmacokinetics 882British Journal of Cancer (1999) 79(5/6), 882-887 © 1999 Cancer Research Campaign Article no. bjoc.1998 Received prior chemo-, immuno-or radiotherapy for at least 4 weeks before study entry; white blood cell (WBC) count ≥ 4000 µl -1 and platelet count ≥ 100 000 µl -1 ; bilirubin ≤ 25 µmol l -1 and aspartate-amino transferase (AST) and alanine-amino transferase (ALT) within 2.5 times the normal upper limit; normal prothrombin time (PT); creatinine clearance ≥ 60 ml min -1 . Written informed consent was obtained from all patients. The protocol was approved by the Medical Ethical Committee of the University Hospital Groningen.Fostriecin was supplied by NCI (Bethesda, MD, USA) as a lyophilized powder and was diluted with 0.9% NaCl to 50 or 100 ml. It was administered as a 60-min intravenous (IV) infusion through an UV-light protected system on days 1-5 at 4-week intervals. The dose was initially escalated according to the Fibonacci scheme, with subsequent dose steps of 2, 4, 6.6, 10 and 12.2 mg m -2 day -1 and thereafter increased to 20 mg m -2 (the protocol was amended during the study to allow more rapid dose escalation). Three patients were entered at each dose level, with a maximum of three additional patients when one out of three experienced dose-limiting toxicity (DLT). When no DLT was observed, ...

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Novel mechanisms of resistance to inhibitors of DNA topoisomerases

Cited by 21 publications

References 19 publications

DNA Cleavage within the MLL Breakpoint Cluster Region Is a Specific Event Which Occurs as Part of Higher-Order Chromatin Fragmentation during the Initial Stages of Apoptosis

DNA Cleavage within the MLL Breakpoint Cluster Region Is a Specific Event Which Occurs as Part of Higher-Order Chromatin Fragmentation during the Initial Stages of Apoptosis

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

Phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin

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