Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic lymphocytic leukemia is a neoplastic disease in which drug resistance invariably occurs. We have studied the uptake and interaction with molecular targets of two drugs, chlorambucil and adriamycin, in CLL lymphocytes and CHO cell lines. Resistance does not appear related to uptake for either drug. Exposure to CLB causes DNA cross-links in the sensitive but not in the resistant cell line. The GSH content of B-CLL lymphocytes is depleted after a 20-hr incubation. An inability to maintain its GSH content may contribute to this cell's vulnerability to CLB. The resistance of CLL lymphocytes to ADR may be related to the undetectable levels of its target enzyme DNA topoisomerase II. Future approaches may involve study of novel anthracyclines, DNA topoisomerase I inhibitors and the development of in vitro predictive tests.
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PMID:Studies on drug resistance in chronic lymphocytic leukemia. 256 Dec 48

A consensus sequence has been derived for vertebrate topoisomerase II cleavage of DNA (Spitzner, J. R. and Muller, M. T. (1988) Nucleic Acid. Res. 16, 5533-5556). An independent sample of 65 topoisomerase II sites (obtained in the absence of topoisomerase II inhibitors) was analyzed and found to match the consensus sequence as well as enzyme sites determined in the presence of the anti-tumor drug 4'-(9-acridinyl-amino)-methanesulfon-m-anisidide (m-AMSA). As originally described, conventional application of the consensus sequence afforded accuracy in the prediction of the locations but not the frequencies of topoisomerase II cleavages. In the present report, we describe a new method which quantitatively discriminates sites from nonsites, called the 'matrix mean' method (the mean match of a site to the matrix of base proportions from the original consensus sequence derivation). Furthermore, we derived a second method, called the 'unique score' model, which predicts frequency of topoisomerase II activity at a cleavage site. In the unique score method both DNA strands of a site are examined to determine the total number of the consensus positions that match on at least one strand of a potential site. From the new data base of 65 topoisomerase II sites, cleavages were scored for relative cleavage strength. Linear regression analysis showed a significant (p less than 0.01) correlation between the unique score and cleavage strength. The study was extended to show that the unique score model accurately and quantitatively predicts topoisomerase II sites either in the absence or presence of m-AMSA using the same consensus sequence.
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PMID:Application of a degenerate consensus sequence to quantify recognition sites by vertebrate DNA topoisomerase II. 256 27

Drug-induced DNA hypermethylation was observed to constitute one component of the response of human tumor cells to toxic concentrations of commonly used cancer chemotherapy agents. In both human lung adenocarcinoma cells (HTB-54) and human rhabdomyosarcoma cells (CCl-136), pulse exposures to the topoisomerase II inhibitors etoposide and nalidixic acid; to the antibiotic doxorubicin; to the microtubule inhibitors vincristine, vinblastine, and colchicine; to the DNA cross-linking agent cisplatinum; to hydroxyurea; and to the antimetabolites 1-beta-D-arabinofuranosylcytosine, 5-fluorouracil, 5-fluorodeoxyuridine, and methotrexate were associated with profound drug-induced DNA hypermethylation. Exposure of human T-lymphocytes (MOLT-4) to toxic pulse doses of 3'-azidodideoxythymidine was associated with similar drug-induced DNA hypermethylation. In every case, drug-induced DNA hypermethylation was observed only when the degree of DNA synthesis inhibition caused by the drug exceeded 90% and when drug levels or duration of exposure was sufficient to kill 90-100% of exposed cells. Drug-induced DNA hypermethylation was shown not to represent a tissue culture phenomenon, since it occurred in vivo during high-dose 1-beta-D-arabinofuranosylcytosine and hydroxyurea treatments in two leukemic patients. Drug-induced alterations in DNA methylation were frequently biphasic, with hypomethylation occurring at drug concentrations which produced mild DNA synthesis inhibition and which killed less than 50% of exposed cells. Exposure to the alkylating agents 1,3-bis(2-chloroethyl)-1-nitrosourea and cyclophosphamide and to the antimetabolites 5-azadeoxycytidine and 6-thioguanine was associated with DNA hypomethylation at all studied concentrations in HTB-54 cells. Drug-induced DNA hypermethylation could be blocked by preexposure to hypomethylating agents administered at nontoxic to mildly toxic concentrations. Drug-induced DNA hypermethylation may be capable of creating drug-resistant phenotypes by inactivating genes the products of which are required for drug cytotoxicity. Perhaps paradoxically, drug-induced DNA hypermethylation may also produce a second class of drug-resistant tumor cells, characterized by overexpression of particular gene products, by potentiating the process of gene amplification.
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PMID:Drug-induced DNA hypermethylation and drug resistance in human tumors. 279 Jul 94

Stimulation of topoisomerase II cleavage activity by antitumor drugs with or without DNA intercalative ability has been tested in vivo on the c-myc proto-oncogene. Two human tumor cell lines (N417 and HL60 cells) were treated with mAMSA, OH-9-ellipticine, VM26, and BD-40 (an aza-ellipticine analog), and DNA breaks were mapped in the gene locus by Southern blot hybridization with c-myc probes. Most of the major cleavage sites induced in vivo by drugs in the 5' end of c-myc were also observed in vitro using purified topoisomerase II and a c-myc gene DNA insert. Moreover, they closely mapped to some DNAse I hypersensitive sites, the presence of which reflects gene activity. DNA from drug treated cells probed with a human beta 1 globin pseudogene, and the c-mos proto-oncogene did not reveal topoisomerase II cleavage bands, suggesting that topoisomerase II-mediated drug activity may correlate with gene activity.
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PMID:In vivo and in vitro stimulation by antitumor drugs of the topoisomerase II-induced cleavage sites in c-myc proto-oncogene. 281 30

We have recently shown that the aggregation factor (AF) from the sponge Geodia cydonium stimulates DNA synthesis in quiescent, dissociated cells from the same organism; this event was correlated with the release of the two second messengers: inositol trisphosphate and diacylglycerol. Here we describe that after binding of the AF to the plasma membrane-bound aggregation receptor, a rapid and drastic increase in the incorporation of 32Pi into a series of proteins in the pore complex-lamina fraction occurs. Addition of the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate, to quiescent cells resulted in a similar stimulation of phosphorylation of nuclear proteins. Among them we have selected one protein with a polypeptide Mr of 170,000 (pp170) for detailed studies. By immunoblotting pp170 was identified as DNA topoisomerase II. In vitro studies with nuclei and purified, homogeneous protein kinase C together with the required activators of this enzyme also showed a phosphorylation of pp170. After phosphorylation, DNA topoisomerase II activity was found to be 2.5-fold that of the non-phosphorylated enzyme. From these data we conclude that protein kinase C is involved in AF induced transmembrane signalling, ultimately leading to an initiation of DNA synthesis.
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PMID:Specific phosphorylation of proteins in pore complex-laminae from the sponge Geodia cydonium by the homologous aggregation factor and phorbol ester. Role of protein kinase C in the phosphorylation of DNA topoisomerase II. 283 45

DNA topoisomerases I and II are nuclear enzymes which modify DNA topology by their ability to break and reseal one or both strands in concert. Each of these enzymes has important functions in DNA replication, and very likely in other genetic processes as well. In addition, each can serve as a cancer chemotherapy target. The plant alkaloid camptothecin traps DNA topoisomerase I in a form which is covalently linked to DNA. Presumably this action is the basis for its anti-tumor effect, although this has not been conclusively demonstrated. The evidence for DNA topoisomerase II as a target for intercalating agents and epipodophyllotoxins is more formidable. Each of these classes of agents traps the enzyme on DNA in a structure referred to as a 'cleavable complex'. Illicit recombination events, as well as induction of an 'SOS-like' response analogous to that found in bacteria, have been suggested as possible mechanisms for cell death following cleavable complex formation. Development of new agents directed at topoisomerase II will depend heavily on understanding the nature of the interaction between the drug, enzyme and DNA. Hypotheses are presented in this paper on this interaction. Intracellular content of topoisomerase II is linked to the ability of the cell to enter a G0-like state, and the inability of malignant cells to undergo such a change may provide part of the basis for therapeutic selectivity. The ability to modulate topoisomerase II levels may provide an opportunity for therapeutic intervention.
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PMID:DNA topoisomerases in cancer therapy. 283 59

Oxazolopyridocarbazole derivatives (OPCd) are intercalating polycyclic molecules related to the anti-tumor drug 9-hydroxyellipticinium (Celiptium). From a pharmacological point of view, OPCd compounds are highly cytotoxic to malignant cultured cells but inactive or only weakly active against experimental tumors in vivo. Extensive physicochemical and biological investigations have been performed in this series including the determination of hydrophobic properties, interaction parameters with DNA and polynucleotides, interaction with DNA topoisomerase II in vitro, diffusion through cell membranes, accessibility to genomic DNA in cells and in chromatin preparations and finally, cytotoxic and anti-tumor activities. Establishment of relationships between physicochemical data and biological properties have been attempted. The results show that all the OPCd compounds display favorable parameters in terms of association constant values to DNA, accessibility to DNA in chromatin structure and permeation through cellular membranes. However, in contrast with intercalating drugs such as m-AMSA, adriamycin and 9-hydroxyellipticinium, OPCd compounds are not able to generate cleavable complexes in DNA through the interaction with topoisomerase II. With respect to design of anti-tumor drugs, these findings indicate that a high association constant value to DNA, the ability to intercalate between DNA base pairs without causing physical damage and an efficient diffusion through cell membranes are not by themselves sufficient for the expression of anti-tumor activity.
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PMID:Relationships between physicochemical and biological properties in a series of oxazolopyridocarbazole derivatives (OPCd); comparison with related anti-tumor agents. 284 46

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)
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PMID:Effect of phorbol ester treatment on drug-induced, topoisomerase II-mediated DNA cleavage in human leukemia cells. 284 55

The specific inhibition of eukaryote DNA topoisomerase II by the anti-cancer drugs VP16, VM26, and 21 other congeners of podophyllotoxin has been extensively studied in this laboratory through the use of alkaline elution and other techniques. A structure-activity relationship has been established for cytotoxicity, single and double strand DNA breakage, and inhibition of the DNA strand passing activity of topoisomerase II. Furthermore, topoisomerase inhibition was measured in four naturally sensitive and resistant human lung carcinoma cells by quantifying the amount of single and double strand DNA breakage produced by VP16 and VM26 in cells and isolated nuclei. A direct correlation between double but not single strand DNA breaks and cytotoxicity was observed for the analogs in A549 human lung adenocarcinoma cells. In fact, some analogs were capable of producing substantial single strand DNA breakage without producing cytotoxicity. A similar correspondence was observed between double strand DNA breaks and cytotoxicity produced by VP16 and VM26 in the naturally sensitive and resistant cell lines. Evidence is also presented suggesting that the association of the drug with enzyme-DNA intermediate complex and the formation of the enzyme-DNA complex alone both reflected equilibrium governed conditions that were readily reversible. These studies support a model based on the proposal that the actual cytotoxic events are genetic alterations caused by possible heterologous subunit exchanges occurring between adjacent enzyme molecules, which result from the stabilization of the intermediate complex, rather than the actual loss of topoisomerase II activity caused by the inhibition. The resistance of normal cells and cells with acquired resistance to the possible clastogenic effects of topoisomerase inhibition may be, in part, related to the low topoisomerase II levels found in such cells. Topoisomerase II may also play a role in gene amplification and tumor cell heterogeneity by serving as a vehicle through which genetic recombination events may occur.
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PMID:Inhibitors of topoisomerase II: structure-activity relationships and mechanism of action of podophyllin congeners. 285 48

It has recently been suggested that topoisomerases could be important targets for several DNA intercalating drugs used in cancer therapy. This prompted us to purify and characterize a type II topoisomerase in a highly tumorigenic transplantable rabbit tumor isolated from a skin carcinoma associated with cottontail rabbit papillomavirus. We have found that the decatenating activity present in tumor cells was 40-100 times higher than that in the rabbit liver, while no activity could be found in skin extracts. The type II topoisomerases purified from tumor and liver cells consist of two subunits with molecular masses of about 160 kDa. The conditions of the reactions of relaxation, unknotting and decatenation catalyzed by these topoisomerases II were found to be similar to those observed with enzymes of other eukaryotic cells. In the course of the purification of the VX2 enzyme, we isolated and characterized a protein of about 30 kDa in whose presence the topoisomerase II was able to catenate very efficiently supercoiled DNA molecules. This protein has the same electrophoretic mobility as an H1-2 histone, and cross-reacts with an anti-H1 antiserum. The VX2 topoisomerase II as well as the VX2 tumor should constitute useful models for assays of antitumoral drugs.
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PMID:A type-II DNA topoisomerase and a catenating protein from the transplantable VX2 carcinoma. 298 98


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