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)

We examined the effects of phorbol ester treatment on topoisomerase II-mediated events in two human leukemia cell lines with different proclivities toward phorbol ester-induced monocytoid differentiation. HL-60 is the parent line that will terminally differentiate; 1E3 is a derived line that will not terminally differentiate. Within 24 h of phorbol ester treatment, etoposide-induced, topoisomerase II-mediated DNA cleavage declined 10-fold, whereas 4'-(9-acridinylamino)-methanesulfon-m-anisidide- induced DNA cleavage declined 3-fold in HL-60. In phorbol-treated 1E3, etoposide-induced DNA cleavage declined only 2-fold, whereas 4'-(9-acridinylamino)methanesulfon-m-anisidide-induced cleavage was barely affected. There was a 2- to 3-fold decline in topoisomerase II activity within the nuclear extracts from phorbol-treated HL-60 cells but not from phorbol-treated 1E3 cells. Immunoblotting experiments with anti-topoisomerase II antibodies indicated that phorbol treatment produced a structural change in the immunoreactive topiosomerase II in HL-60 nuclear extracts but produced no change in 1E3 topoisomerase II. Phorbol ester treatment also produced a decline in the level of topoisomerase II gene expression in HL-60 but not in 1E3 cells. By contrast, the cytotoxicity of etoposide in both lines was decreased following phorbol treatment. Thus, phorbols may uncouple the mechanisms linking drug-induced, topoisomerase II-DNA cleavable complex stabilization with drug-induced cytotoxicity, particularly in 1E3.
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PMID:Phorbol ester effects on topoisomerase II activity and gene expression in HL-60 human leukemia cells with different proclivities toward monocytoid differentiation. 217 56

A camptothecin-resistant subline of P388 leukemia (P388/CPT) was developed by repeated transplantation of P388 cells in mice treated with therapeutic doses of camptothecin. In mice bearing the resistant tumor, a maximally tolerated dose of camptothecin produced no net reduction in tumor cell burden, in contrast to a 5-log cell kill in the parental P388 (P388/S). The IC50 of camptothecin, as determined by colony formation assays of cultured cells, was 8 times greater for the cloned P388/CPT cell line than for P388/S. P388/CPT cells were not cross-resistant to other antineoplastic agents, including topoisomerase II inhibitors. The type I topoisomerases purified from P388/CPT and P388/S cells were identical with respect to molecular weight, specific activity, in vitro camptothecin sensitivity, and DNA cleavage specificity. Camptothecin induced fewer protein-associated DNA single-strand breaks in the resistant cells than in the wild-type P388 cells. Topoisomerase I mRNA, immunoreactivity, and extractable enzymatic activity were 2-4 times lower for P388/CPT cells than for P388/S cells. As resistance to camptothecin developed, topoisomerase I extractable activity decreased, concomitant with an increase in topoisomerase II extractable activity. Furthermore, the appearance of camptothecin resistance was associated with specific rearrangements of the topoisomerase I gene. These results suggest that development of resistance to inhibitors of topoisomerase I can occur by down-regulation of the target enzyme, thus reducing the production of lethal enzyme-mediated DNA damage. The enhanced topoisomerase II activity in these cells suggests that resistance to camptothecin may be overcome by co-treatment with topoisomerase II inhibitors.
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PMID:Development of a stable camptothecin-resistant subline of P388 leukemia with reduced topoisomerase I content. 217 65

Mitoxantrone, a cytotoxic anthracenedione derivative, has given clinical evidence of beneficial activity in breast cancer, lymphoma and leukaemia. Several different mechanisms of action have been suggested to account for this. In addition to intercalation, biological effects such as electrostatic interactions with DNA, DNA-protein cross-links, immunosuppressive activities, inhibition of topoisomerase II, prostaglandin biosynthesis and calcium release have been described. Various methods of drug monitoring in biological fluids and tissues are available: the highest sensitivity has been achieved with high performance liquid chromatography with electrochemical detection, radioimmunoassay and enzyme linked immunosorbent assay. Early pharmacokinetic studies of mitoxantrone in experimental animals using radioactive material showed an extensive tissue distribution and a long terminal plasma half-life. The best fit for the plasma concentration-time curve in humans is achieved in a 3-compartment model. All studies reported a short absorption half-life of between 4.1 and 10.7 minutes, with the distribution phase being between 0.3 and 3.1 hours. In contrast, the values of the terminal half-life are quite variable, ranging from 8.9 hours to 9 days. Differences might be attributed to assay sensitivity, number and weighting of data points beyond 24 hours and coadministration drugs. Many studies showed a very large volume of distribution with sequestration of mitoxantrone in a deep tissue compartment. In autopsy studies, relatively high tissue concentrations have been measured in liver, bone marrow, heart, lung, spleen and kidney. Bile is the major route for the elimination of mitoxantrone, with lesser amounts excreted in the urine. Several metabolites have been separated, 2 of which were identified as the monocarboxylic and dicarboxylic acid derivatives. Mitoxantrone is usually administered by rapid intravenous infusion at 3-weekly intervals; other regimens include continuous infusion, daily repeated doses or weekly administration. In peritoneal carcinosis, the pharmacological advantage of intraperitoneal administration is clear. The optimal regimen for different disease categories with respect to efficacy and side-effects remains to be determined in future clinical trials.
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PMID:Pharmacokinetics and metabolism of mitoxantrone. A review. 218 7

Amsacrine is a DNA intercalating agent which is active against a number of tumours in mice and is used for the treatment of leukaemia in humans. In its DNA-bound form, amsacrine efficiently quenches the fluorescence of ethidium. Fluorescence lifetime studies demonstrate two populations of DNA-bound ethidium. The first, whose fluorescence lifetime is constant at approx. 3 ns and whose proportion increases with increasing amsacrine binding ratio, may comprise molecules bound in close proximity to amsacrine. The second, whose fluorescence lifetime is longer and variable (10-24 ns) and whose proportion decreases with increasing amsacrine binding ratio, may comprise molecules three or more base-pairs away from ethidium. Studies with a number of derivatives of 9-anilinoacridine containing different anilino substituents suggest that the observed wide variation in quenching capacity is correlated with the magnitude of the substituent dipole moment in a particular direction. Consideration of the geometry of the DNA-binding complex indicates that the negative pole of a dipole established in the anilino ring is directed towards a positively charged site on the ethidium molecule. Quenching of ethidium fluorescence may therefore occur where an electron-transfer complex has formed between ethidium and amsacrine molecules. To ascertain whether electron-transfer complex formation is biologically important in the amsacrine series, ethidium quenching has been quantitated and compared with activity against a transplantable neoplasm in mice, the Lewis lung carcinoma. Compounds which strongly quench ethidium fluorescence are in general highly active antitumour agents. The results are discussed in terms of a model where amsacrine has both a DNA-binding and a protein-binding domain, the latter possibly interacting by formation of an electron-transfer complex. The most likely protein-binding domain is on the enzyme topoisomerase II, the target for its cytotoxic activity.
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PMID:The possible role of electron-transfer complexes in the antitumour action of amsacrine analogues. 220 43

Ethyl 5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin- 7-ylcarbamate, 2-hydroxyethanesulfonate, hydrate (NSC 370147) was evaluated for antitumor activity against a spectrum of tumor systems in culture and in mice. NSC 370147 was cytotoxic to a variety of mouse and human cell lines at nanomolar concentrations. The compound exhibited good in vivo antitumor activity against several murine tumors (P388 and L1210 leukemia, colon 11/A and 36, mammary 16/C, and M5076 sarcoma). Activity was largely independent of route of administration but favored a prolonged treatment schedule. NSC 370147 was as active against murine leukemia sublines resistant to Adriamycin, amsacrine, vincristine, melphalan, cisplatin, methotrexate, and CI-920 (a topoisomerase II inhibitor) as against the corresponding parental lines. Only the 1-beta-D-arabinofuranosylcytosine-resistant P388 subline exhibited any cross-resistance to NSC 370147. NSC 370147 has a spectrum of activity similar to that of vincristine and, unlike vincristine, is active against multidrug-resistant cell lines. Therefore, NSC 370147 is a candidate for clinical trial because of its favorable activity compared to vincristine, its effectiveness against multidrug-resistant cells, and its retention of activity for p.o. administration.
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PMID:Antitumor activity of ethyl 5-amino-1,2-dihydro-2-methyl-3-phenyl-pyrido [3,4-b]pyrazin-7-ylcarbamate, 2-hydroxyethanesulfonate, hydrate (NSC 370147) against selected tumor systems in culture and in mice. 233 19

Defining specific biochemical targets of active antineoplastic agents could aid in discovering better anticancer therapy and more thoroughly understanding the biochemical basis of malignancy. Through a series of cellular and biochemical studies, we and others have identified the nuclear enzyme topoisomerase II as the target of several active agents, including 4'-(9-acridinylamino) methanesulfon-m-anisidide (m-AMSA). The interference with topoisomerase II produced by m-AMSA can be quantified in whole cells exposed to m-AMSA by using the alkaline elution technique to measure DNA cleavage. Antimetabolites such as ara-C, hydroxyurea, and 5-azacytidine can augment m-AMSA-induced, topoisomerase II-mediated DNA cleavage and, concurrently, m-AMSA-induced cell killing. Studies in proliferating and quiescent human cells and an m-AMSA-sensitive/resistant human leukemia cell pair further support the hypothesis that a connection exists between topoisomerase II-mediated DNA cleavage and the mechanism by which m-AMSA kills cells. Pharmacologic or hormonal modification of specific biochemical processes critical to drug-induced cytotoxicity may enhance the therapeutic index of clinically useful agents.
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PMID:Intercalator-induced, topoisomerase II-mediated DNA cleavage and its modification by antineoplastic antimetabolites. 242 89

The relationship between DNA topoisomerase II activity and drug resistance was studied in cloned cell lines of Adriamycin (ADR)-sensitive and -resistant P388 leukemia; drug resistant P388/ADR/3 (clone 3) and P388/ADR/7 (clone 7) cells are 5- and 10-fold more resistant to ADR than the sensitive cell line P388/4 (Cancer Res., 46: 2978, 1986). Topoisomerase II catalytic activity in crude nuclear extracts was reduced in drug-resistant cells as determined qualitatively by decatenation of kDNA. Using the centrifugal method fo quantitative analysis, topoisomerase II catalytic activity (mean +/- SE) was 81 +/- 10 units/mg total nuclear protein in sensitive cells, 29 +/- 2 units/mg total nuclear protein in resistant clone 3 cells, and 16 +/- 2 units/mg total nuclear protein in resistant clone 7 cells; these differences were highly significant (P less than 0.005). Similarly, quantitative analysis of DNA cleavage activity using 3' 32P-end-labeled pBR322 restriction fragments showed that drug-stimulated topoisomerase II cleavage activity in nuclear extracts from sensitive cells was approximately 1.7- and 2.9-fold greater than that from resistant clone 3 and 7 cells, respectively. Western blot analysis of nuclear extracts from the three cell lines using antibody against the C-terminal half of recombinant-prepared human topoisomerase II polypeptide revealed reduced immunoreactivity of topoisomerase II protein in the drug-resistant cells. These data suggest that reduced topoisomerase II activity in resistant cells, which may represent quantitative reduction of the enzyme, may be another property contributing to multifactorial drug resistance in these cells.
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PMID:Direct correlation between DNA topoisomerase II activity and cytotoxicity in adriamycin-sensitive and -resistant P388 leukemia cell lines. 253 93

Our human T-cell leukemia line, CEM/VM-1, selected for resistance to VM-26 (teniposide), is cross-resistant to several drugs that interact with topoisomerase II, including VP-16 (etoposide), 4'-(9-acridinylamino)methanesulphon-m-anisidide, daunorubicin, and mitoxantrone. However, in contrast to cell lines exhibiting multidrug resistance (MDR) associated with overexpression of P-glycoprotein, this line is not cross-resistant to the Vinca alkaloids, is not impaired in drug accumulation, and does not overexpress the mdrl gene (Cancer Res., 47: 1297, 5455, 1987). More recently we found that nuclear extracts of these cells exhibit decreased topoisomerase II catalytic and cleavage activity, compared to the drug-sensitive line (Biochemistry, 1988). These results suggest that an alteration in topoisomerase II or a modulator of this enzyme may be responsible for this altered topoisomerase II-form of multidrug resistance (at-MDR). In the present work, we studied the somatic cell genetics of at-MDR. We produced hybrid cell lines by polyethylene glycol-mediated fusion of the CEM/VM-1 line with a hypoxanthine-guanine phosphoribosyl transferase-deficient, ouabain-resistant CEM line (CEM.AG1.OU1.5) that exhibits VM-26 sensitivity. Ten of the hybrid lines that grew in selective medium were randomly chosen for expansion and four were analyzed for both DNA content by flow cytometry and VM-26 sensitivity in a 72-h growth inhibition assay. The hybrid lines all contained approximately 2x DNA compared to unfused controls, indicating that the fusions were successful. The IC50 for VM-26 in 3 of the 4 lines was the same as that of the sensitive controls, ranging from 4.7 to 7.4 x 10(-8) M, and another was 76 x 10(-8) M. These data indicate that drug sensitivity was reconstituted by the hybridization procedure. By comparison, the VM-26 IC50 values in the CEM/VM-1 cells and CEM/VM-1 x CEM/VM-1 control "fusions" were 360 and 750 x 10(-8) M, respectively. To determine whether a topoisomerase II-mediated function was reconstituted in the hybrids, we measured drug-stimulated DNA cleavage ("cleavable complex formation"). Using 32P-labeled pBR322 DNA as substrate with nuclear extracts from drug sensitive cells, 100 microM VM-26 maximally stimulated DNA cleavage by approximately 11-fold compared to no-drug controls.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Genetic characterization of the multidrug-resistant phenotype of VM-26-resistant human leukemic cells. 253 2

Several fused tri- and tetracyclic quinolines (I and II) with [2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino or [3-(N,N-dimethylamino)propyl]amino side chains were prepared, and their DNA intercalative properties, KB cytotoxicity, antitumor activity (P388 leukemia), and ability to induce topoisomerase II dependent DNA cleavage were investigated. Some compounds having both intercalative ability and KB cytotoxicity were found to be inactive in vivo. However, a positive correlation was seen between the ability to induce topoisomerase II dependent DNA cleavage and antitumor activity in vivo. The indeno- (13a), benzofuro- (21a), and benzothieno- (22a) quinoline derivatives exhibited potent antitumor activities in vitro and in vivo, comparable to those of m-AMSA. They also intercalate DNA and induce topoisomerase II dependent DNA cleavage. Extended screening of 13a showed it to be active against solid tumors such as M5076 sarcoma, B16 melanoma, and colon 38 carcinoma.
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PMID:Synthesis and antitumor activity of fused tetracyclic quinoline derivatives. 1. 254 58

A new cytotoxic acridine alkaloid that exhibited antitumor activity in vivo was isolated from a marine Dercitus species sponge collected at a depth of 160 m in the Bahamas. This violet alkaloid, designated dercitin, inhibited the proliferation of cultured murine and human leukemia, lung, and colon tumor cells at nM concentrations (IC50 values of 63-150 nM) and prolonged the life of mice bearing ascitic P388 tumors (%T/C = 170, 5 mg/kg, i.p., QD1-9). Dercitin was also active against i.p. B16 melanoma and modestly inhibited the growth of s.c. Lewis lung carcinoma on the same schedule. DNA blocked the antiproliferative effects of the agent in culture, and incorporation studies indicated that dercitin disrupted DNA and RNA synthesis with less effects on protein synthesis, similar to the effects of known DNA intercalators. After 1-h exposure to 400 nM dercitin, the rates of incorporation of [3H]uridine, [3H]thymidine, and [3H]leucine by cultured P388 cells were inhibited 83, 61, and 23%, respectively. Equilibrium dialysis indicated that dercitin bound calf thymus DNA with an affinity of 3.1 microM and maximal binding of 0.20 mol dercitin/mol base pair. Binding involved intercalation as evidenced by ability to relax supercoiled phi X174 DNA (half maximal concentration for dercitin relaxation was 36 nM). The effects of dercitin on DNA mobility were reversible, and complete relaxation of DNA with topoisomerase I in the presence of dercitin followed by phenol extraction resulted in the appearance of supercoiled DNA. Dercitin, at microM concentrations, had a small effect in the K+-sodium dodecyl sulfate assay using cultured P388 cells, suggesting minimal inhibition of topoisomerase activity. But, dercitin completely inhibited DNA polymerase I/DNase nick translation of DNA at 1 microM. Relaxation of DNA at a given concentration was greater than inhibition of nick translation suggesting that the effects of dercitin on enzyme activity were secondary to changes in DNA conformation. Results indicate that dercitin is a new marine natural product that probably exerts its biological effects through intercalation into nucleic acids.
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PMID:Antitumor activity and nucleic acid binding properties of dercitin, a new acridine alkaloid isolated from a marine Dercitus species sponge. 254 17


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