Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The thymine oxidative lesion-5-hydroxymethyluracil (HMUra)-was measured in urine collected from cancer patients. These patients all received chemotherapy using Adriamycin. Adriamycin (ADR) intercalates DNA coils and interferes with normal cell metabolism through diverse biochemical mechanisms that may explain its different actions. The anticancer action of ADR could derive from its interaction with topoisomerase II, resulting in DNA nicking followed by DNA fragmentation and apoptosis. Side effects of ADR-mainly its cardiotoxicity-may derive from the fact that ADR generates superoxide and hydroxyl radicals in two ways: redox-cycling and a Haber-Weiss type reaction due to Fe-ADR complexes. The oxygen free radicals, particularly .OH, are thought to be produced by ADR directly in genomic material and attack all its components. 5-Hydroxymethyluracil is a thymine lesion provoked by these attacks, and it has been proposed as a marker of DNA alterations. In this article, we report the results of a study involving 14 cancer patients treated with ADR. We found that urine HMUra is significantly increased by the anticancer therapy (HMUra (nmol/24 h): 74.4 9.46 vs. 96.3 8.74; p < .01), this increase reveals a higher risk of mutagenesis. Our study is the first to show an in vivo alteration of DNA by ADR. Results also show that thiobarbituric acid reactants increase significantly, and that the vitamin levels for retinol and alpha-tocopherol, which are antioxidant vitamins, are lower at the end of chemotherapy. We suggest to supplement these patients with vitamins A and E, and selenium to reduce the side effects of ADR.
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PMID:5-Hydroxymethyluracil excretion, plasma TBARS and plasma antioxidant vitamins in adriamycin-treated patients. 874 84

Inhibitors of calcium-calmodulin-dependent processes, 1-[N,O-bis(1,5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-piperazine KN-62 and trifluoperazine (TFP), at non-cytotoxic concentrations (2 and 5 microM, respectively) enhanced etoposide (VP-16) cytotoxicity in Adriamycin-resistant (HL-60/ADR0.05) cells (3- to > 50-fold). In contrast to TFP, the inhibitor KN-62 was able to reverse resistance in HL-60/ADR0.05 cells at VP-16 concentrations that produced equivalent cytotoxicity in sensitive (HL-60/S) cells. Unlike TFP, the cellular accumulation of VP-16 in the presence of KN-62 was enhanced 1.5- to 2-fold in HL-60/S (MDR1 -ve) and HL-60/ADR0.05 (MDR1 +ve) cells. To achieve equivalent cytotoxicity, levels of VP-16 in the resistant cells were > 4-fold lower in the presence of KN-62 compared with treatment with VP-16 alone. The sensitizing effects of both KN-62 and TFP were due to enhancement (2- to 4-fold) of VP-16-induced topoisomerase II (TOPO II)-mediated DNA cleavable complex formation, and depletion of the 170 kDa (alpha) TOPO II isoform. The DNA damage induced by VP-16 in the presence of KN-62 or TFP resulted in the rapid induction of apoptosis and depletion of cells in "S" phase of the cell cycle. Both 5 microM TFP and 2 microM KN-62 enhanced the phosphorylation of 170 kDa TOPO II 1.6-fold and 1.5-fold, respectively. Results suggest that the inhibitory effect of KN-62 or TFP on calcium-calmodulin-dependent processes may be mechanistically involved in sensitizing resistant cells to VP-16 by enhancing TOPO II-mediated DNA damage.
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PMID:Cellular events involved in the sensitization of etoposide-resistant cells by inhibitors of calcium-calmodulin-dependent processes. Role for effects on apoptosis, DNA cleavable complex, and phosphorylation. 895 49

A series of 1-azolylalkyl-4(1H)-quinolones has been synthesized and evaluated for cytotoxic activity both in vitro and in vivo. The effects on cytotoxicity of varying substitution on the quinoline moiety was investigated. The insertion of a 5-amino group proved to be the most effective modification, resulting in a several-fold increase in cytotoxicity in vitro. Previously reported results indicated that the activity of this class of compounds may involve topoisomerase inhibition, but investigation of the current compounds has ruled out this possibility. One compound, 13, showed in vitro cytotoxicity notably superior to Adriamycin, however it demonstrated only slight or no in vivo efficacy depending on the model used.
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PMID:Cytotoxic quinolines (Part 3). Synthesis of 1-azolylalkyl-4(1H)-quinolones as cytotoxic agents. 901 Jun 18

Probucol [(4,4'-(-(isopropylidenedithio) bis (2,6-di-t-butylphenol)], a hypolipidemic drug, was evaluated for its effects on the clastogenic activity of ADM in Swiss albino mice. Male mice were treated i.p. with different doses (25, 50 and 100 mg/kg, body weight/day) of probucol for 7 days. Some of the mice in each dose group of probucol and those in the positive control group were injected i.p. with Adriamycin (ADM, 8 mg/kg, body weight) and killed after 24 hr. Femoral cells of mice were collected and studied for the frequency of micronuclei and the ratio of polychromatic erythrocytes to Normochromatic erythrocytes. Furthermore, proteins, DNA, RNA, Malondialdehyde (MDA) and non-protein sulfhydryl (NP-SH) levels were determined in the hepatic cells. Probucol treatment failed to induce any significant clastogenic, cytotoxic and biochemical changes. However, pre-treatment with probucol was found to reduce the ADM-induced micronuclei without any alteration in its cytotoxicity. The DNA, RNA, proteins and NP-SH levels in the hepatic cells of these animals were increased and the MDA concentrations were reduced. The inhibition of ADM-induced clastogenicity by probucol may be attributed to its lipids lowering, iron chelating, free radical scavenging and topoisomerase-II-depleting action.
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PMID:Effect of probucol on the cytological and biochemical changes induced by adriamycin in Swiss albino mice. 902 75

We have established an Adriamycin (ADM)-resistant small cell lung cancer (SCLC) cell line, SBC-3/ADM 100, which shows multifactorial mechanisms of resistance to ADM, such as over-expression of P-glycoprotein, an enhanced detoxifying system and a decrease in topoisomerase II activity. In the present study, we confirmed that SBC-3/ADM 100 showed collateral sensitivity to methotrexate and TNP-351, a new antifolate, though this cell line showed a typical multidrug resistance (MDR) pattern. We also demonstrated a faster uptake and higher accumulation (1.3-fold) of TNP-351 in the SBC-3/ADM 100 cells than those in the parent SBC-3 cells. These results explain one of the mechanisms for collateral sensitivity in the resistant cells. Furthermore, this cell line was found to have no cross-resistance to edatrexate and minimal cross-resistance to trimetrexate, 254-S (cisplatin analog), 5-fluorouacil and 4-hydroperoxyifosfamide. These drugs will have clinical importance in patients with SCLC who were previously treated with an ADM-containing regimen. Thus, antifolates, especially TNP-351 and edatrexate, can be expected to eradicate residual multidrug resistant SCLC cells selected by ADM.
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PMID:Growth inhibitory effects of antifolates against an adriamycin-resistant human small cell lung cancer cell line. 922 90

Doxorubicin is a therapeutically useful anticancer drug that exerts multiple biological effects. Its antitumor and cardiotoxic properties have been ascribed to anthracycline-mediated free radical damage to DNA and membranes. Evidence for this idea comes in part from the selection by doxorubicin from stationary phase yeast cells of mutants (petites) deficient in mitochondrial respiration and therefore defective in free radical generation. However, doxorubicin also binds to DNA topoisomerase II, converting the enzyme into a DNA damaging agent through the trapping of a covalent enzyme-DNA complex termed the 'cleavable complex.' We have used yeast to determine whether stabilization of cleavable complexes plays a role in doxorubicin action and cytotoxicity. A plasmid-borne yeast TOP2 gene was mutagenized with hydroxylamine and used to transform drug-permeable yeast strain JN394t2-4, which carries a temperature-sensitive top2-4 mutation in its chromosomal TOP2 gene. Selection in growth medium at the nonpermissive temperature of 35 degrees in the presence of doxorubicin resulted in the isolation of plasmid-borne top2 mutants specifying functional doxorubicin-resistant DNA topoisomerase II. Single-point changes of Gly748 to Glu or Ala642 to Ser in yeast topoisomerase II, which lie in and adjacent to the CAP-like DNA binding domain, respectively, were identified as responsible for resistance to doxorubicin, implicating these regions in drug action. None of the mutants selected in JN394t2-4, which has a rad52 defect in double-strand DNA break repair, was respiration-deficient. We conclude that topoisomerase II is an intracellular target for doxorubicin and that the genetic background and/or cell proliferation status can determine the relative importance of topoisomerase II- versus free radical-killing.
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PMID:Identification of yeast DNA topoisomerase II mutants resistant to the antitumor drug doxorubicin: implications for the mechanisms of doxorubicin action and cytotoxicity. 938 29

We examined the genetic and biochemical bases for drug resistance and the order of appearance of different mechanisms underlying the increasingly more resistant murine erythroleukemia cell lines established in Adriamycin (ADR). In the first-step low-level resistant cell line PC4-A5 (able to grow in 5 ng/mL ADR), there was a 2-fold reduction in topoisomerase IIalpha and topoisomerase IIbeta mRNA levels, as well as topoisomerase IIalpha protein and activity levels as compared with the parental cell line. The topoisomerase IIalpha activity levels remained reduced as the cells became increasingly more resistant. In contrast, the topoisomerase II mRNA and protein levels returned to approximately the parental levels in resistant cells growing in higher drug concentrations (40-160 ng/mL). Parental cells expressed the multidrug resistance protein (MRP), but beginning with PC4-A5 MRP expression decreased and remained reduced in increasingly resistant cell lines. At high levels of ADR resistance, the cells expressed the mdr3 gene concomitant with the appearance of vincristine resistance and energy-dependent daunomycin and vincristine efflux. Glutathione levels, internal pH, and expression of the major vault protein (MVP) remained unchanged in all cell lines. Fluorescence microscopy revealed no alterations in daunomycin distribution or vesicle numbers between the parental and resistant cell lines. Different resistance mechanisms emerge sequentially as cells become more resistant to ADR; the mechanisms are retained during the development of multidrug resistance (MDR). In intermediate-level MDR cell lines (PC4-A10 and PC4-A20), resistance involves an as yet undetermined mechanism(s).
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PMID:Emergence of different mechanisms of resistance in the evolution of multidrug resistance in murine erythroleukemia cell lines. 939 72

N-benzyladriamycin-14-valerate (AD 198) is pharmacologically superior to Adriamycin (ADR) based upon comparable cytotoxicity, decreased cardiotoxicity and the ability of AD 198 to circumvent multidrug resistance conferred by either P-glycoprotein overexpression or reduced topoisomerase II activity. AD 198, however, suffers from systemic lability of the 14-O-valerate moiety to enzymatic and non-enzymatic cleavage to yield N-benzyladriamycin (AD 288), which is more similar to ADR in activity. The purpose of this study was to determine whether stability of the ester linkage could be achieved while preserving the favorable characteristics of AD 198 by using a series of N-benzylated ADR congeners containing 14-O-acyl substitutions of incrementally shorter carbon chain lengths. Results from this study indicate that the linear five-carbon valerate substitution is the minimum length necessary to circumvent P-glycoprotein and prevent inhibition of topoisomerase II activity. In addition, although AD 198 is not a pro-drug of AD 288, intracellular 14-O-acyl cleavage appears to contribute to the cytotoxicity of AD 198.
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PMID:Cytotoxicity and intracellular biotransformation of N-benzyladriamycin-14-valerate (AD 198) are modulated by changes in 14-O-acyl chain length. 949 93

Previous studies have demonstrated decreased levels of DNA topoisomerase II alpha protein and messenger RNA in the Adriamycin-resistant P388 murine leukemia cell line P388/ADR/7 compared to the sensitive P388/4 cell line. An allelic fusion event involving the topoisomerase II alpha and the retinoic acid receptor a genes has been identified in these cells that probably contributes to the decreased topoisomerase II activity in P388/ADR/7 cells. However, this allelic mutation may be a minor contributor or even incidental to the resistance phenotype, since these cells display other candidate mechanisms of resistance, including increased P-glycoprotein, increased glutathione-S-transferase activity and an increased onset of DNA repair. To establish a role for topoisomerase II alpha in mediating the Adriamycin resistance phenotype, complementation of the mutant allele was attempted by transfecting the murine P388/ADR/7 cells with a human topoisomerase II alpha expression construct under the control of the human metallothionein IIA promoter. The majority of transfected cell lines that were obtained by selection in hygromycin B contained copies of the integrated expression construct that were rearranged. Only two of thirty-two transfected cell lines were found to contain a single, unrearranged copy of the human topoisomerase II alpha cDNA. P388/ADR/7 cell lines carrying an integrated, intact human topoisomerase II alpha expression vector were more sensitive to Adriamycin, daunorubicin, mitoxantrone, and etoposide, but not to actinomycin D and vincristine compared to control cells transfected with vector alone or cell lines with rearranged topoisomerase II alpha expression constructs. These findings suggest that topoisomerase II alpha is a selective and significant contributor to multifactorial resistance.
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PMID:Selective sensitization of adriamycin-resistant P388 murine leukemia cells to antineoplastic agents following transfection with human DNA topoisomerase II alpha. 949 16

A human stomach-adenocarcinoma cell line (MKN-45) was selected for resistance to Adriamycin by stepwise exposure to increasing concentrations of this agent. The resulting cell line (MKN/ADR) exhibited a high level of cross-resistance to topoisomerase II (topo II)-targeted drugs such as Adriamycin, mitoxantrone, and etoposide but showed no cross-resistance to other chemotherapeutic agents such as cisplatin, carboplatin, 5-fluorouracil, or mitomycin-C. P-glycoprotein encoded by the mdr-1 gene was not overexpressed in the MKN/ADR cell line. The doubling time of the MKN/ADR cell line (2.1 days) increased only slightly as compared with that of the MKN cell line (1.7 days). The patterns of cross-resistance to various chemotherapeutic agents led us to examine the cellular contents of topo II in both the drug-sensitive and the drug-resistant cells. Extractable topo II enzyme activity was 3-fold lower in MKN/ADR cells as compared with the parental MKN cells. Levels of topoisomerase I (topo I) catalytic activity were similar in both wild-type MKN and drug-resistant MKN/ADR cells. Southern-blot analysis of genomic DNA probed with topo IIalpha or IIbeta showed no sign of either gene rearrangement or hypermethylation. Northern-blot analysis revealed that both topo IIalpha and topo IIbeta mRNA transcripts were essentially identical in the MKN and MKN/ADR cells. In contrast, Western-blot analysis revealed an approximately 20-fold lower level of topo IIalpha in drug-resistant cells as compared with drug-sensitive cells, whereas topo IIbeta levels were similar in both lines. Moreover, the amount of in vivo topo IIalpha-DNA covalent complexes formed in the presence of etoposide was also approximately 20-fold lower in drug-resistant cells. No mutation was detected in the promoter region of the topo IIalpha gene in resistant cells as compared with sensitive cells. Thus, low levels of topo IIalpha polypeptide cannot be ascribed to changes in the mRNA levels. Collectively, the data suggest that a quantitative reduction in topo IIalpha may contribute to the resistance of MKN cells to Adriamycin and other topo II-targeted drugs.
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PMID:Reduced activity of topoisomerase II in an Adriamycin-resistant human stomach-adenocarcinoma cell line. 952 30


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