Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ledakrin [1-nitro-9-(3'-dimethylamino-N-propylamino)acridine], an antitumor drug of the 1-nitro-9-aminoacridine family, was able to induce DNA-protein crosslinks in intact L1210 leukemia cells, as demonstrated by the potassium-dodecyl sulfate precipitation technique. Ledakrin-induced DNA-protein crosslinks were not readily reversible nor were they accompanied by DNA double-strand breaks. Also, ledakrin produced virtually no crosslinks in isolated nuclei. Ledakrin-induced DNA-protein crosslinks seemed not to be mediated by topoisomerase II, unlike well-established effects of a chemically related antitumor drug, 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA). Four ledakrin analogs of divergent cytotoxic potencies also induced DNA-protein crosslinks but not DNA double-strand breaks in intact L1210 cells. A significant positive correlation existed between the ability of ledakrin and its 1-nitro analogs to induced DNA-protein crosslinks and the antiproliferative effects of these drugs. The results are consistent with the previously shown ability of 1-nitro-9-aminoacridines to covalently bind to macromolecules after metabolic activation in the cell. In addition to previously demonstrated DNA interstrand crosslinks and monofunctional adducts, DNA-protein crosslinks constitute another type of DNA lesion induced by 1-nitro-9-aminoacridines.
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PMID:Induction of DNA-protein crosslinks by antitumor 1-nitro-9-aminoacridines in L1210 leukemia cells. 255 39

The effect of three acridine derivatives, 9-aminoacridine (9AA), 4'-(9-acridinylamino)-methanesulphon-O-anisidide (O-AMSA) and quinacrine were compared in their ability to protect against the cytotoxicity of amsacrine, 9-[[2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino)-N,5-dimethyl-4- acridine-carboxamide (CI-921), N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (AC), etoposide, mitoxantrone and doxorubicin. Cytotoxicity was measured in vitro by clonogenic survival assay and in vivo by life extension assays. All three acridine derivatives protected a Lewis lung cell line in vitro against CI-921, with 9AA having the highest activity. Cellular uptake of [14C] CI-921 by cultured Lewis lung cells was unaffected by 9AA, and slightly stimulated by O-AMSA and quinacrine. 9AA protected Lewis lung cells in vitro against the cytotoxicity of amsacrine, CI-921, AC and etoposide, partially against mitoxantrone but not against doxorubicin. A similar result was obtained with the human melanoma cell line MM96, where 9AA protected against CI-921 but not against doxorubicin toxicity. 9AA protected P388 leukaemia in vivo against amsacrine, CI-921 and AC cytotoxicity, partially against etoposide but not against mitoxantrone or doxorubicin. 9AA also protected against animal toxicity caused by high dose amsacrine and partially against CI-921 toxicity. It is hypothesized that DNA intercalating chemoprotectors act by restricting the conformational flexibility of the DNA and thus the ability of topoisomerase II to form a 'cleavable complex' in which the DNA is covalently linked to the enzyme.
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PMID:Chemoprotection by 9-aminoacridine derivatives against the cytotoxicity of topoisomerase II-directed drugs. 256 Oct 99

The drug-sensitivity and cross-resistance profiles of cloned cell lines of Adriamycin-sensitive and -resistant P388 murine leukemia have been further characterized. A range of drug sensitivity that was more than 50,000-fold was observed for Adriamycin-sensitive cells; the most potent cytotoxic agent was the Adriamycin analog, 3'-(3-cyano-4-morpholinyl)-3'-deamino adriamycin, and the least active compound was vinblastine. Adriamycin-resistant cells, which express the multidrug resistance phenotype, were cross-resistant to the DNA topoisomerase II interactive drugs: actinomycin D, daunorubicin, mitoxantrone, etoposide, and 4'-(9-acridinyl-amino)methanesulfon-m-anisidide, to the vinca alkaloids: vincristine and vinblastine, and to colchicine but not to the Adriamycin analog, 3'-(3-cyano-4-morpholinyl)-3'-deamino adriamycin or the alkylating agent, melphalan. These findings are consistent with other studies suggesting that 3'-(3-cyano-4-morpholinyl)-3'-deamino adriamycin acts as an alkylating agent. Studies with DNA topoisomerase II interactive agents, including mitoxantrone, the DNA intercalator, and etoposide, the epipodophyllotoxin, showed that, as with Adriamycin, cytotoxicity correlated closely with the formation of DNA double-strand breaks.
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PMID:Further characterization of drug-sensitivity and cross-resistance profiles of cloned cell lines of Adriamycin-sensitive and -resistant P388 leukemia. 264 Jan 53

Amsacrine, an acridine derivative used clinically in the treatment of acute leukaemia, has formed the basis for the development of further compounds with high activity against experimental solid tumours, one of which is currently in clinical trial. We have compared the ability of these drugs to cause point mutations in bacteria, 'petite' mutations in yeast and mutations in mammalian cells. Several of the compounds are frameshift mutagens in Salmonella typhimurium TA1537 while some cause 'petite' mutagenesis in Saccharomyces cerevisiae. All are highly clastogenic and have significant mutagenic activity at the 6-thioguanine locus in cultured V79 Chinese hamster fibroblasts following 1 h drug exposures. None are mutagenic at the ouabain locus of these cells. The relationship between different indicators of mutagenicity has been studied using an additional set of amsacrine analogues, some of which are mutagenic in S. typhimurium TA98. There is a highly significant relationship between mutation frequency (measured as resistance to 6-thioguanine) and either cytotoxicity (D37 values in a clonogenic assay) or clastogenicity (ability to induce micronuclei). However, there is no correlation with mutagenicity in microbial systems. The results suggest that the cytotoxicity, clastogenicity and mutagenic activity of the amsacrine analogues is mediated by similar mechanisms, probably involving the enzyme DNA topoisomerase II.
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PMID:Mutagenicity profiles of newer amsacrine analogues with activity against solid tumours: comparison of microbial and mammalian systems. 264 76

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and pharmacodynamics of etoposide are reviewed. Etoposide, although similar in chemical structure to podophyllotoxin, has a different mechanism of cytotoxicity compared with its parent compound. Etoposide may stabilize type II topoisomerase-DNA complexes, preventing rejoining of single- and double-strand DNA breaks. Etoposide may also require cellular activation into intermediates, which then bind to DNA and disrupt cellular function. Oral etoposide has an average bioavailability of 50% (range, 17%-137%), with substantial intrapatient and interpatient variability. Etoposide is widely distributed in the body and is highly bound to plasma proteins (greater than 95%). Approximately 50% (range, 20%-81%) of an etoposide dose is recovered in the urine as parent drug or glucuronide, with the remainder of the dose being unaccounted for. The disposition of etoposide in patients with renal and hepatic dysfunction is discussed. Etoposide is effective in combination with other agents against lung cancer, and response rates of 90% in small-cell lung cancer have been observed. When etoposide is used in combination with other agents, response rates of approximately 80% have been observed in patients with testicular cancer. The activity of etoposide in treating leukemia, lymphoma, and breast and ovarian carcinomas and other tumors is discussed. The impact of etoposide on prolonging survival in lung and testicular cancer is addressed, and studies evaluating the pharmacodynamics of etoposide are described. Adverse effects associated with etoposide therapy include myelosuppression, alopecia, nausea and vomiting, mucositis, and hypotension after rapid intravenous administration. Etoposide has demonstrated considerable clinical efficacy against a broad spectrum of tumors.
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PMID:Etoposide: an update. 279 80

N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (AC; NSC 601316) is a chemically novel antitumour agent which is thought to interact with DNA topoisomerase II and which has DNA binding properties which are distinct from other acridine derivatives such as amsacrine and its disubstituted analogue CI-921. AC is one of the most active agents, experimental or clinical, against the Lewis lung carcinoma in mice. AC is the first acridine derivative in our hands to show higher activity against cultured Lewis lung cells than against leukaemia lines. AC is more active against two human leukaemia cell lines (U-937 and Jurkat) than against a melanoma line (MM-96) and is inactive against the HT-29 human colon line. With all cell lines tested, cytotoxicity was higher at AC concentrations of 3-6 microM than at 15-20 microM. AC at a concentration of 20 microM inhibited the cytotoxicity of amsacrine and CI-921, but not that of another topoisomerase-directed drug doxorubicin. A Lewis lung line which had been cultured for a long period was less sensitive than a line freshly isolated from mice, but sensitivity of the cultured line recovered after it was multiply passaged in vivo. Long-term cultures may therefore be less appropriate than short-term cultures for predicting effectiveness of AC in vivo.
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PMID:Selectivity of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide towards Lewis lung carcinoma and human tumour cell lines in vitro. 270 82

Treatment of human HL-60 or KG1A leukemia cells with the topoisomerase II inhibitor etoposide resulted in extensive DNA degradation. When DNA integrity was analyzed by agarose gel electrophoresis, a nucleosomal ladder became evident 1.5-2 h after addition of etoposide to cells, increased in intensity over 6 h, and persisted at 24 h. Six h after addition of the drug, 94 +/- 4% of the cells excluded trypan blue even though as much as 90% of the DNA had been degraded to oligosomal fragments. Exposure of cells to 10 micrograms/ml (17 microM) etoposide for as little as 45 min was sufficient to induce this DNA damage 4 h later. Preincubation with dinitrophenol abolished the effect of etoposide, suggesting that an energy-requiring step occurred prior to or during the endonucleolytic cleavage. In contrast, the effect of etoposide was not prevented by preincubation of HL-60 cells with the RNA synthesis inhibitor 5,6-dichloro-1-beta-ribofuranosylbenzimidazole or the protein synthesis inhibitors cycloheximide or puromycin. On the contrary, high concentrations of 5,6-dichloro-1-beta-ribofuranosylbenzimidazole, cycloheximide, or puromycin by themselves induced the same endonucleolytic cleavage, as did a variety of diverse cytotoxic agents, including camptothecin (0.1 microM), colcemid (0.1 microgram/ml), cis-platinum (20 microM), methotrexate (1 microM), and 1-beta-D-arabinofuranosylcytosine (3 microM). These results suggest that endonucleolytic DNA damage by a preexisting cellular enzyme occurs soon after treatment of HL-60 cells with any of a variety of cytotoxic agents. The observation that a variety of nuclear proteins [including poly(ADP-ribose) polymerase, lamin B, topoisomerase I, topoisomerase II, and histone H1] are degraded concomitant with the DNA fragmentation calls into question the selectivity of the degradative process for DNA. The implications of these results for (a) current theories which focus upon endonucleolytic damage of DNA as a critical early event during cell death, and (b) use of topoisomerase-directed drugs to map topoisomerase-binding sites in active chromatin are discussed.
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PMID:Induction of endonucleolytic DNA cleavage in human acute myelogenous leukemia cells by etoposide, camptothecin, and other cytotoxic anticancer drugs: a cautionary note. 279 Aug

The identification of topoisomerase II as a target of antineoplastic drug therapy is traced from the original observations by Ross et al. (1,2) in murine leukemia cells through studies with m-AMSA-resistant human leukemia cells. Recently developed quantitative biochemical assays of topoisomerase II activity and the susceptibility of topoisomerase II to the effects of m-AMSA have allowed the principles identified in murine and human leukemia cell culture systems to be applied to clinical material; a prospective trial is testing the utility of such assays for individualizing antineoplastic drug therapy.
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PMID:Topoisomerase II as a target of antileukemic drugs. 281 36

The nuclear enzyme, topoisomerase II, is the major site of action for cancer chemotherapy agents such as etoposide, teniposide, and a variety of intercalating agents. These compounds cause the enzyme to cleave DNA, forming a DNA-protein complex that may be a key step leading to cell death. It is apparently unique as a chemotherapy target, since drug potency diminishes with decreasing enzyme activity. It was thus of interest to examine the topoisomerase content and drug-induced DNA cleavage in freshly obtained human leukemia cells and to compare the obtained data with the results of similar studies performed in well-characterized human leukemia cell lines. The human T-lymphoblast line, CCRF-CEM, was more than 100-fold more sensitive to the DNA-cleavage effect of etoposide than the cells of the 13 leukemic patients examined. One of the leukemia lines (HL-60) and a lymphoblastoid line (RPMI-7666) were somewhat less sensitive than cells of the CCRF-CEM cells, but were still 10-fold more sensitive than the patients studied. The relative insensitivity of the freshly obtained cells could not be accounted for by differences with respect to drug uptake but were associated with markedly reduced topoisomerase-II content as assayed by immunoblotting using a mouse polyclonal serum against topoisomerase II. Heterogeneity was observed in the sensitivities of patients' cells with respect to both drug-induced DNA cleavage and enzyme content. The observed differences between cultured cell lines and patients' cells may have been related to their proliferative status. Etoposide potency in normal resting lymphocytes resembles that observed in circulating leukemia cells. However, following mitogenesis with phytohemagglutinin and interleukin-2, proliferating lymphocytes become as sensitive to etoposide as cultured cell lines with regard to DNA cleavage. This effect was accompanied by an increase in topoisomerase-II content. Our data thus support the hypothesis that topoisomerase-II content may be an important determinant of cell sensitivity to certain classes of chemotherapy agents. Efforts to stimulate topoisomerase-II content may improve the therapeutic efficacy of these drugs.
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PMID:Etoposide-induced DNA cleavage in human leukemia cells. 282 74

Agents that slow cellular proliferation usually stimulate myeloid differentiation. The demonstration in this report of an anomalous inhibitory behavior of the epipodophyllotoxin VP16-213, an agent known to inhibit the enzyme DNA topoisomerase II, prompted us to investigate the role of this enzyme in both changes in DNA supercoiling and in DNA strand breakage and reunion events occurring during the induction of neutrophil-granulocyte differentiation. We recently reported that retinoic acid, an inducer of granulocytic differentiation, stimulates transient relaxation of DNA supercoiling. We now show that this is associated with the formation of small numbers of protein-linked DNA breaks (a characteristic of topoisomerase reactions). Both events are perturbed by VP16-213, and since this agent inhibits subsequent differentiation, these observations raise the possibility of a role for DNA topoisomerase II in granulocytic differentiation. The possible relevance of these findings to mechanisms of leukemogenesis is discussed.
Leukemia 1987 Sep
PMID:Evidence for the involvement of DNA topoisomerase II in neutrophil-granulocyte differentiation. 282 25


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