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)

Short-term (2-6 h) exposure of human promyelocytic HL-60 cell cultures to the DNA topoisomerase I inhibitor camptothecin (0.05-0.5 microgram/ml) or to the topoisomerase II inhibitor, teniposide (VM-26; 0.3-3.0 micrograms/ml) or 4'-(9-acridinylamino)methanesulfon-m-anisidide (amsacrine; 0.8 microgram/ml) triggered rapid degradation of DNA specifically in S-phase cells. As a result of the selective death of S-phase cells, only G1 cells remained in these cultures. On the other hand, mitoxantrone (0.02-0.4 microgram/ml) or doxorubicin (adriamycin; 0.4-10.0 micrograms/ml) did not induce DNA degradation in S phase but arrested HL-60 cells in S and G2 phases. In contrast to HL-60 cells, human lymphocytic leukemic MOLT-4 cells responded to all of these drugs (camptothecin, teniposide, amsacrine, mitoxantrone, and adriamycin) at all concentrations tested, invariably by being arrested in G2 and S phases and also by entering a higher DNA ploidy cycle. The data illustrate the differences in the sensitivity of S-phase cells in myelogenous versus lymphocytic leukemic lines to both DNA topoisomerase I and II inhibitors and emphasize the tissue (leukemia type)-specific factors that modulate the cytostatic and cytotoxic effects of these inhibitors. The qualitatively different response of HL-60 cells to camptothecin, teniposide, or amsacrine (by rapidly triggered DNA degradation in S phase) as compared to mitoxantrone or adriamycin (by cell arrest in G2 and S) suggests that, despite the generally assumed common mode of action attributed to these drugs (i.e., via stabilization of the cleavable DNA-topoisomerase complexes), there are significant differences in the mechanisms by which they exert cytostatic/cytotoxic effects.
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PMID:Camptothecin, teniposide, or 4'-(9-acridinylamino)-3-methanesulfon-m-anisidide, but not mitoxantrone or doxorubicin, induces degradation of nuclear DNA in the S phase of HL-60 cells. 199 59

Some tetracyclic quinolines (9 and 14) with a [2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino side chain were prepared and their deoxyribonucleic acid (DNA) intercalative properties, KB cytotoxicity, antitumor activity (P388 leukemia), and ability to induce topoisomerase II dependent DNA cleavage were investigated. The indoloquinoline derivative 9 exhibited the most potent activity (dose = 6.3 mg, T/C% = 300) in this series. The steric structural features of the chromophores of the compounds previously and newly synthesized were studied by a computer-associated molecular graphics technique. Relationships between the steric structural features of the chromophores and biological activities are also discussed.
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PMID:Synthesis and antitumor activity of fused quinoline derivatives. 208 86

Mitoxantrone, an anthracenedione derivative, has been used for preclinical and clinical studies from the end of the 1970s. Several working mechanisms are suggested such as intercalation and electrostatic interactions with DNA with or without involvement of topoisomerase II, immunosuppressive effects and inhibition of prostacyclin synthesis. Efficacy of mitoxantrone alone or in combination with other chemotherapeutic drugs has been especially demonstrated in patients with breast cancer, leukemia and lymphoma. Locoregional (but not intrathecal) therapy with this drug is possible because it is not a vesicant. It has an improved tolerability profile compared with doxorubicin. Dose-limiting toxicity is myelotoxicity and mucositis. Therefore this drug has recently also been used in high doses with bone marrow support and in combination with hematopoietic growth factors. Cardiotoxicity is less frequent than after doxorubicin and daunorubicin. However, cardiac function tests are warranted after cumulative doses greater than 160 mg/m2 or earlier if additional risk factors, namely previous mediastinal irradiation, anthracycline therapy or cardiovascular disease, are present.
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PMID:Mitoxantrone: bluebeard for malignancies. 215 49

A multidrug-resistant variant of the P388 leukemia cell line exhibits multiple biochemical changes, including reduced drug accumulation and markedly reduced DNA strand breakage induced by anthracyclines. To investigate whether the reduced formation of drug-induced DNA breaks was due to alteration of DNA topoisomerase II activity, nuclear extracts and partially purified enzymes from the sensitive line and the resistant subline were compared. DNA topoisomerase II activity in 0.35 M NaCl nuclear extracts from sensitive cells was approximately 1.7 times higher than that found in extracts from resistant cells, as determined by ability to unknot P4 phage DNA. In addition, it was found that teniposide-stimulated topoisomerase II DNA cleavage activity of nuclear extract from resistant cells was at least 10-fold lower than that from sensitive cells. This differential sensitivity paralleled a similar drug response of nuclei, as determined by the alkaline elution method. However, partially purified DNA topoisomerase II showed similar drug sensitivity in both cell lines. This finding suggests the presence of a modulating factor, which may be lost during purification. These results, indicating a reduction of both catalytic activity and DNA cleavage activity of DNA topoisomerase II in P388 multidrug-resistant cells, emphasize the importance of DNa topoisomerase function in the resistance mechanism. Thus, the concomitant involvement of multiple mechanisms could explain the high degree of resistance of these cells.
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PMID:Evidence of DNA topoisomerase II-dependent mechanisms of multidrug resistance in P388 leukemia cells. 215 5

Murine P388 (P) leukemia cell lines resistant to amsacrine (P/AMSA), dactinomycin (P/DACT), and doxorubicin (P/DOX) were compared with the parental strain in their sensitivity to a number of derivatives of amsacrine. The P/DACT cell line, which shows the characteristics of a transport-mediated multidrug-resistant cell line, was cross-resistant to vincristine, doxorubicin, etoposide, and a number of acridine-substituted amsacrine derivatives, but was sensitive in vitro and in vivo to amsacrine and its analog CI-921. The P/DOX cell line was cross-resistant to amsacrine but showed a similar pattern of cross-resistance to that of P/DACT in its in vitro response to amsacrine derivatives. In contrast, the P/AMSA line was substantially cross-resistant (from 27- to 146-fold) to all acridine-substituted amsacrine derivatives. However, when the substituents on the anilino side chain of amsacrine were changed, the in vitro cross-resistance of the P/AMSA line could be substantially reduced and even overcome. Derivatives with low cross-resistance ratios were tested in vivo against the P/AMSA leukemia and, in contrast to amsacrine and CI-921, were found to be active. Since the target enzyme for amsacrine action, topoisomerase II, is thought to be structurally modified in the P/AMSA line as well as in some other multidrug-resistant lines, these results suggest the feasibility of tailoring topoisomerase II-directed drugs specifically for the altered enzymes in resistant cells. New drug design approaches are therefore available for overcoming two major types of multidrug resistance.
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PMID:Design of DNA intercalators to overcome topoisomerase II-mediated multidrug resistance. 215 84

The antileukemia drug amsacrine and seven analogues were tested for in vitro activity against five multidrug-resistant human leukemia cell sublines (two derived from each of two Jurkat parent lines and one from the K562 line) and the corresponding parent lines (Jurkat, K562, and P388 leukemia). Resistant cell lines were derived by exposure to either amsacrine or doxorubicin. The resistance factor was calculated as the ratio of the mean IC50 value for the resistant cell line to that for the parent line. IC50 was defined as the concentration of drug inhibiting cell growth to 50% of that in control (drug-free) cultures. Patterns of cross-resistance were visualized by plotting the deviations of resistance factors from the mean resistance factor, on a logarithmic scale. Considerable variations in resistance factors were noted for each cell subline as the amsacrine substituents were altered. Four main patterns were evident: a transport-related multidrug-resistance pattern (three sublines), a pattern similar to that for a murine P388 leukemia subline resistant to amsacrine, and two patterns not observed previously. Since some of the sublines tested showed evidence of altered topoisomerase II activity, it appears that changes in the resistance pattern in these lines may reflect changes in the stability of the ternary complexes formed by the drug, the altered enzyme, and the DNA. The resistance factor was reduced from more than 100-fold to about 13-fold in three of the sublines tested and from eightfold to twofold in two others. This finding suggests that appropriate drug design may overcome several forms of multidrug resistance in human leukemia and other types of cancer.
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PMID:Multiple patterns of resistance of human leukemia cell sublines to amsacrine analogues. 215 26

Genistein, an in vitro inhibitor of topoisomerase II and tyrosine kinases, suppressed growth and induced differentiation in HL-205 cells, a clonal population of the human promyelocytic HL-60 leukemia cells, and in K-562-J cells, a clonal population of the human erythroid K-562 leukemia cells. Maturing HL-205 cells acquired either granulocytic or monocytic markers, namely, reactivity with the murine OKM1 monoclonal antibody, expression of nitroblue tetrazolium dye reduction, and staining for nonspecific esterase. The maturing K-562-J cells stained with benzidine, which indicates the presence of hemoglobin, an erythroid maturation marker. Although the acquisition of the maturation markers in both HL-205 and K-562-J cells was time dependent up to 6 days, the kinetics of this induction differed between the two cell types. Despite the in vitro inhibitory effect of genistein, treatment of either HL-205 or K-562-J cells with 150 micrograms/ml genistein for up to 16 h did not alter topoisomerase II activity (as determined by the unknotting assay) in their nuclear extracts. Analysis with the anti-phosphotyrosine PY-20 murine monoclonal antibody indicated that treatment of K-562-J cells with genistein decreased the reactivity of the antibody with two of the cellular proteins. However, no reactivity with the PY-20 antibody was detected in untreated or genistein-treated HL-205 cells. An early event in the HL-205 and K-562-J cells, occurring after only 1 h of treatment with 30-200 micrograms/ml genistein, was the induction of DNA damage as measured by an alkaline elution assay. This damage may be a contributing factor in the genistein-induced cell differentiation in the HL-205 and K-562-J cells.
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PMID:Induction of differentiation and DNA strand breakage in human HL-60 and K-562 leukemia cells by genistein. 215 95

CEM leukemia cells selected for resistance to VM-26 (CEM/VM-1) are cross-resistant to various other DNA topoisomerase II inhibitors but not to Vinca alkaloids. Since DNA topoisomerase II is a major protein of the nuclear matrix, we asked if alterations in nuclear matrix topoisomerase II might be important in this form of multidrug resistance. Pretreatment of drug-sensitive CEM cells for 2 h with either 5 microM VM-26 or 3 microM m-AMSA reduced the specific activity of newly replicated DNA on the nuclear matrix by 75 and 50%, respectively, relative to that of the bulk DNA. However, neither VM-26 nor m-AMSA affected the relative specific activity of nascent DNA isolated from the nuclear matrices of drug-resistant CEM/VM-1 cells. The decatenating and unknotting activities of DNA topoisomerase II were 6- and 7-fold lower, respectively, in the nuclear matrix preparations from the CEM/VM-1 cells compared to parental CEM cells. Western blot analysis revealed that the amount of immunoreactive topoisomerase II in the nuclear matrices of the CEM/VM-1 cells was decreased 3.2-fold relative to that in CEM cells, but there was no significant difference in the amount of enzyme present in the nonmatrix (1.5 M salt soluble) fractions of nuclei from these cell lines. Increasing the NaCl concentration used in the matrix isolation procedure from 0.2 to 1.8 M resulted in a progressive decrease in the specific activity of topoisomerase II in matrices of CEM/VM-1 but not CEM cells, which suggested that the association of the enzyme with the matrix is altered in the resistant cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Decreased nuclear matrix DNA topoisomerase II in human leukemia cells resistant to VM-26 and m-AMSA. 216 74

The mechanism of action of 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin (MX2) was examined in a human leukemia cell line (K562) and its Adriamycin (ADM)-resistant subline (K562/ADM). ADM and MX2 showed an equivalent antitumor effect against K562. K562/ADM was highly resistant to ADM. In cellular pharmacokinetic studies, MX2 showed faster and greater influx than did ADM in both K562 and K562/ADM. The efflux of ADM was rapid in K562/ADM but not in K562. On the other hand, the efflux of MX2 was rapid in both cell lines. The formation of DNA single-strand breaks and double-strand breaks by ADM was significantly lower in K562/ADM than K562. On the other hand, formation of those breaks by MX2 was not decreased. Although some of the DNA breaks induced by MX2 were resealed, there was no difference in the degree of resealing in K562 and K562/ADM cells. On the other hand, most of the small number of DNA breaks in K562/ADM induced by ADM were resealed. The topoisomerase II activity in K562 and K562/ADM was not significantly different. It is concluded that MX2 conquers multidrug resistance by rapid influx following a higher frequency of formation of DNA single- and double-strand breaks in K562/ADM cells.
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PMID:3'-Deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin conquers multidrug resistance by rapid influx following higher frequency of formation of DNA single- and double-strand breaks. 216 45

Topoisomerase II has been suggested to have a role in the early events of differentiation. This possibility was evaluated by measuring the effects of inhibitors of topoisomerase II on the induction of the differentiation of WEHI-3B D+ monomyelocytic leukemia cells. Differentiation of this cell line was induced along the granulocytic pathway by treatment with the topoisomerase II inhibitors novobiocin (150-300 microM), teniposide (20-50 nM), etoposide (0.1 microM), elsamicin (0.5 microM), and doxorubicin (40 nM). Maturation was assessed by the morphological appearance of mature forms of the granulocytic lineage, an increase in cell surface Fc receptors, the ability to reduce nitroblue tetrazolium, and the loss of proliferative capacity. In contrast, the non-topoisomerase II-reactive agent cisplatin and the topoisomerase I-reactive drug camptothecin did not cause the maturation of WEHI-3B D+ cells. Aclacinomycin A and retinoic acid, which are known efficacious inducers of the differentiation of this cell line, affected topoisomerase II extracted from WEHI-3B D+ cells in vitro, causing concentration-dependent inhibition of the strand-passing activity of the enzyme. Treatment of WEHI-3B D+ cells with novobiocin at 150 microM for 3 h or with teniposide at 50 nM for 24 h resulted in a 2- to 3-fold increase in etoposide-induced protein-DNA cross-links. Nuclear proteins in 0.35 M NaCl extracts from cells treated with novobiocin at 150 microM for 3 h or with teniposide at 50 nM for 24 h showed a slight increase in topoisomerase II activity compared to untreated cells. No changes in topoisomerase II levels, as measured by immunoblotting, were detected after treatment of WEHI-3B D+ cells with 150 microM novobiocin or 50 nM teniposide during the first 2 days of treatment. At day 3 of treatment, however, a decrease in topoisomerase II was observed in cells treated with either drug, possibly due to decreased cellular proliferation consequent to cell differentiation. The findings support the conclusion that topoisomerase II may have a role in the induction of granulocytic differentiation of WEHI-3B D+ leukemia cells.
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PMID:Induction of the differentiation of WEHI-3B D+ monomyelocytic leukemia cells by inhibitors of topoisomerase II. 217 8


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