Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interest in DNA-intercalating ligands as anti-cancer drugs has developed greatly since the clinical success of doxorubicin. However, despite a great deal of 'rational design' of synthetic DNA-intercalators, only a few such compounds have proved clinically useful. This review briefly surveys the history of DNA-intercalators as clinically-used anti-cancer drugs, summarizes the known structure-experimental activity relationships and modes of action, and concludes that a factor in the slow progress is that much of the work on these compounds has been carried out by chemists, who were generally more interested in ligand/DNA interactions than drug development. Future development of the class rests on a careful consideration of the biochemical reasons behind the common limitations of the present drugs. The most important are: the inherent resistance of non-cycling cells, the rapid development (even by cycling cells) of resistance by the expression of both P-glycoprotein and altered topoisomerase II, limitations on drug distribution to and transport into tumours, low extravascular pH in tumours and the cardiotoxic side-effects of quinonoid chromophores. These considerations provide a set of constraints on physicochemical properties which must be considered in future design. However, within these constraints, there are useful future avenues for the development of DNA-intercalators as anti-cancer drugs. These include: (i) the production of improved topoisomerase inhibitors (by consideration of drug/protein as well as drug/DNA interactions); (ii) the development of reductively-activated chromophores as hypoxia-selective agents; and (iii) the use of DNA-intercalators of known DNA binding orientation as 'carriers' for the delivery of other reactive functionality specifically (sequence-, regio- and site-specifically) to DNA.
Anticancer Drug Des 1989 Dec
PMID:DNA-intercalating ligands as anti-cancer drugs: prospects for future design. 269 99

The effects of alpha-difluoromethylornithine (DFMO), an ornithine analogue which is an ornithine decarboxylase inhibitor, on the actions of the topoisomerase II-reactive agents 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) and etoposide (VP-16) were investigated in 2 murine L1210 leukemia lines and 2 human HL-60 leukemia lines. One of the human lines was resistant to the cytotoxic and DNA cleaving effects of m-AMSA (HL-60/AMSA). In all 4 lines, alpha-DFMO depleted cellular putrescine and spermidine to nondetectable levels. VP-16-induced DNA cleavage (quantified using alkaline elution) was decreased in all lines following alpha-DFMO treatment. The m-AMSA-induced DNA cleavage was decreased in one of the L1210 lines and in the HL-60 line sensitive to m-AMSA; m-AMSA-induced DNA cleavage was increased in the other L1210 line. The low frequency of m-AMSA-induced DNA cleavage produced in HL-60/AMSA was unaffected by alpha-DFMO treatment. Alterations in drug-mediated DNA effects induced by alpha-DFMO could not be uniformly explained by alpha-DFMO-induced alterations in m-AMSA or VP-16 cellular uptake, as indicated by direct measurements of cell-associated drug or results of DNA cleavage assays in nuclei isolated from alpha-DFMO-treated cells. Exogenous putrescine prevented the effects of alpha-DFMO on drug-induced DNA cleavage, substantiating polyamine depletion as the cause of the altered frequency of DNA cleavage. Cytotoxicity assays in 2 of the lines demonstrated that drug-induced reductions in colony-forming ability paralleled drug-induced DNA cleavage. (2R,5R)-6-heptyne-2,5-diamine, a putrescine analogue which is also an ornithine decarboxylase inhibitor, was also used to deplete polyamine levels in HL-60. (2R,5R)-6-heptyne-2,5-diamine was more potent than alpha-DFMO and produced effects on m-AMSA- and VP-16-induced DNA cleavage and cytotoxicity identical to those produced by alpha-DFMO.
Cancer Res 1987 Dec 15
PMID:Effect of polyamine depletion by alpha-difluoromethylornithine or (2R,5R)-6-heptyne-2,5-diamine on drug-induced topoisomerase II-mediated DNA cleavage and cytotoxicity in human and murine leukemia cells. 282 33

Topoisomerase II was purified from an amsacrine-resistant mutant of P388 leukemia. A procedure has been developed which allows the rapid purification of nearly homogeneous enzyme in quantities sufficient for enzyme studies or production of specific antisera. The purified topoisomerase II migrated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis as two bands with apparent molecular masses of 180 (p180) and 170 kDa (p170); both proteins unknotted P4 DNA in an ATP-dependent manner and displayed amsacrine-stimulated covalent attachment to DNA. Staphylococcus V8 protease cleavage patterns of p170 and p180 showed distinct differences. Specific polyclonal antibodies to either p170 or p180 recognized very selectively the form of the enzyme used to generate the antibodies. Immunoblotting with these specific antibodies showed that both p180 and p170 were present in cells lysed immediately in boiling sodium dodecyl sulfate. Comparison of the purified topoisomerase II from amsacrine-resistant P388 with that from amsacrine-sensitive P388 demonstrated that each cell type contained both p180 and p170; however, the relative amounts of the two proteins were consistently different in the two cell types. The data strongly suggest that p170 is not a proteolytic fragment of p180. Thus, P388 cells appear to contain two distinct forms of topoisomerase II.
J Biol Chem 1987 Dec 05
PMID:Purification of topoisomerase II from amsacrine-resistant P388 leukemia cells. Evidence for two forms of the enzyme. 282 4

The ability of a noncytotoxic dose of ara-C to modulate the amount of 4'-(9-acridinylamino)-methanesulfon-m-anisidide (m-AMSA)- or etoposide-induced topoisomerase II-mediated DNA cleavage and cytotoxicity was examined in m-AMSA-sensitive and -resistant HL-60 human leukemia cells. Ara-C pretreatment (0.1 microM x 48 hr) sensitized m-AMSA-sensitive cells to the cytotoxicity and DNA cleavage produced by both m-AMSA and etoposide. The actions of m-AMSA in the m-AMSA-resistant cells were affected minimally by ara-C. By contrast, ara-C enhanced etoposide-induced DNA cleavage and, to an even greater extent, etoposide-induced cytotoxicity in m-AMSA-resistant cells. These cells were only minimally cross-resistant to etoposide. Ara-C did not affect the cellular uptake of m-AMSA or etoposide, the amount of 0.35 M NaCl-extractable nuclear topoisomerase II activity from either cell line, or the ability of this enzyme activity to covalently bind to DNA in the presence of the drugs, m-AMSA- and etoposide-induced DNA cleavage is thought to result from drug-induced stabilization of a topoisomerase II-DNA complex. The ability of ara-C to modulate this effect and associated cytotoxicity appears to be mediated by the effects of ara-C on cellular targets other than topoisomerase II but which are important to topoisomerase II-mediated events, such as protein-associated DNA cleavage. A good candidate for such a target may be cellular chromatin.
Biochem Pharmacol 1987 Dec 01
PMID:Effect of 1-beta-D-arabinofuranosylcytosine (ara-C) on nuclear topoisomerase II activity and on the DNA cleavage and cytotoxicity produced by 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) and etoposide in m-AMSA-sensitive and -resistant human leukemia cells. 282 13

We characterized a DNA repair system in frog oocytes by comicroinjection of UV-irradiated pBR322 DNA and radiolabeled nucleotides. Repair synthesis was monitored by incorporation of label into recovered pBR322 DNA and by a novel method in which the removal of UV photoproducts was determined from the shift of DNA topoisomers that occurs during gel electrophoresis upon repair of these lesions. We investigated the effects of several drugs in the oocyte system and found that although novobiocin, an inhibitor of topoisomerase II, was an effective inhibitor of repair, VM-26, another inhibitor of topoisomerase II, was not. In addition, the topoisomerase I inhibitor camptothecin had no effect on repair in this system. Finally, circular DNA (either supercoiled or nicked circular) was repaired at least 50 times more rapidly than linear DNA.
Mol Cell Biol 1987 Dec
PMID:Repair of UV-induced lesions in Xenopus laevis oocytes. 283 Apr 88

Tumor-promoting phorbol esters such as phorbol 12-myristate 13-acetate (PMA) induce the monocytoid differentiation of HL-60 human leukemia cells. The cellular receptor for PMA is protein kinase C. However, cellular events distal to protein kinase C phosphorylation are also critical steps toward differentiation. These events may include specific programs of oncogene transcription that have been associated with phorbol ester-induced leukemic cell differentiation. Recently, it has been found that topoisomerase II could be activated by protein kinase C-mediated serine phosphorylation and that PMA treatment of HL-60 cells enhanced extractable topoisomerase II from these cells. Additionally, topoisomerase II-reactive antineoplastic drugs could block PMA-induced differentiation of HL-60. This enzyme has been implicated in gene regulation, and drug-induced, topoisomerase II-mediated DNA cleavage sites have been identified within cellular oncogenes. Thus, topoisomerase II could play a critical role in the signal transduction cascade leading from PMA-protein kinase interaction to monocytoid differentiation. We have examined this relationship between topoisomerase II and PMA-induced differentiation through measurements of drug-induced, topoisomerase II-mediated DNA cleavage (via alkaline elution) in PMA-treated HL-60 cells. Etoposide-induced DNA cleavage was reduced 10-fold in HL-60 cells treated with 10 nM PMA for 24 h. Neither dimethyl sulfoxide (which produces granulocytoid differentiation) nor non-differentiation-inducing phorbol esters could produce this effect. The decreased cleavage was not due to a PMA-induced inhibition of cell-associated etoposide and was demonstrable in nuclei isolated from PMA-treated cells. The decrease was not simply related to decreased cellular proliferation rate as reflected in the inhibition of DNA synthesis because conditions leading to marked inhibition of DNA synthesis did not necessarily inhibit etoposide-induced DNA cleavage. By contrast, lower concentrations of PMA inhibited etoposide-mediated DNA cleavage disproportionately compared with PMA effects on DNA synthesis. Interestingly, PMA reduced cleavage induced by the topoisomerase II-reactive DNA intercalator 4'-(9-acridinylamino)methanesulfon-m-anisidide by 2-fold, suggesting that specific drug-DNA interactions could partially overcome the PMA-induced effect that resulted in decreased etoposide-induced, topoisomerase II-mediated DNA cleavage. Nuclear proteins in 0.35 M NaCl extracts from untreated or PMA-treated HL-60 cells were virtually identical in topoisomerase II activity and in topoisomerase II-associated drug sensitivity.(ABSTRACT TRUNCATED AT 400 WORDS)
Cancer Res 1988 Dec 01
PMID:Effect of phorbol ester treatment on drug-induced, topoisomerase II-mediated DNA cleavage in human leukemia cells. 284 55

In this study, we show that human cytomegalovirus DNA synthesis is inhibited in infected confluent human embryonic lung cells treated with the DNA-intercalative topoisomerase II inhibitor 4-9'-(acridinylamino)methanesulfon-m-anisidide (m-AMSA). Similar inhibitory effects were observed with VM-26, a nonintercalative topoisomerase II inhibitor. This antiviral effect is not attributable to cytotoxic effects per se. Furthermore, m-AMSA appears to have a notably irreversible inhibitory effect on human cytomegalovirus DNA replication. No inhibition of viral DNA synthesis was observed with o-AMSA, a DNA-intercalative isomer of m-AMSA that does not inhibit topoisomerase II.
J Virol 1988 Dec
PMID:Two specific topoisomerase II inhibitors prevent replication of human cytomegalovirus DNA: an implied role in replication of the viral genome. 284 90

The supercoiling of 2 micron DNA in yeast by a process or processes that generate positively and negatively supercoiled domains was shown by the use of yeast DNA topoisomerase mutants expressing Escherichia coli DNA topoisomerase I, an enzyme that relaxes negative supercoils specifically. Intracellular 2 micron DNA becomes positively supercoiled in yeast top1 top2 ts strains expressing the E. coli enzyme when neither one of the yeast DNA topoisomerases I and II is functional. Examination of the linking number distributions of plasmids bearing the inducible promoters of GAL1 and GAL10 genes indicates that the generation of supercoiled domains of opposite signs is related to transcription.
Cell 1988 Dec 02
PMID:Supercoiling of intracellular DNA can occur in eukaryotic cells. 284 73

Metabolism studies of the antitumor drug etoposide show the formation of metabolites in the lactone ring, which are probably not important for the drug's mechanism of action, and oxidative transformations in the dimethoxyphenol ring (E ring), which lead to products that can cause DNA damage and may play a role in the drug's mechanism of action. The cytotoxicity of etoposide is caused by the induction of DNA damage. The occurrence of the DNA lesions can be explained by the capacity of the drug to interfere with the scission-reunion reaction of mammalian topoisomerase II by stabilizing a cleavable complex.
J Natl Cancer Inst 1988 Dec 07
PMID:Mechanism of action of antitumor drug etoposide: a review. 284 32

A family of repetitive extragenic palindromic (REP) sequences is composed of hundreds of copies distributed throughout the chromosome. Their palindromic nature and conservation suggested that they are specifically recognized by a protein(s). We have identified DNA gyrase [DNA topoisomerase (ATP-hydrolysing), EC 5.99.1.3] as one of the REP-binding proteins. Gyrase has at least a 10-fold higher affinity for DNA containing REP sequences than for DNA not containing REP sequences. Binding effectiveness correlates directly with the number of REP sequences in the DNA. DNase I footprinting shows that gyrase protects 205 base pairs on a REP-containing DNA fragment enclosing the REP sequences. In agreement with the above results, a comparison of the REP consensus sequence with the sequence of previously identified pBR322 "strong" gyrase cleavage sites reveals a high degree of homology. Because REP sequences are numerous and found throughout the genome, we suggest they have physiological functions mediated through their interaction with gyrase, such as being sites of action for the maintenance of DNA supercoiling. In addition, we speculate that these interactions may be of a structural nature, such as involvement in the higher-order structure of the bacterial chromosome.
Proc Natl Acad Sci U S A 1988 Dec
PMID:DNA gyrase binds to the family of prokaryotic repetitive extragenic palindromic sequences. 284 43


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