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

---

Query: EC:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In furtherance of our SAR study on the chemistry and antitumor activity of fused nitrogen heteroaromatic compounds, a series of linear, methyl-substituted derivatives of 5H- and 6H-indolo[2,3-b]quinolines were synthesized according to the modified Graebe-Ullmann reaction. To establish the relationship between the physicochemical and biological activities of indolo[2,3-b]quinolines, their lipophilic properties, cytotoxic and antimicrobial activity, and ability to induce topoisomerase II dependent pSP65 DNA cleavage in vitro were investigated. We found that the antimicrobial and cytotoxic activity of indolo[2,3-b]quinolines was strongly influenced by the position, and the number of methyl substituents and the presence of methyl group at pyridine nitrogen was essential for the cytotoxicity of these compounds. All indolo[2,3-b]quinolines belonging to the 5H series, i.e., bearing a methyl group on the pyridine nitrogen, showed significant activity against procaryotic and eucaryotic organisms. They inhibited the growth of Gram-positive bacteria and pathogenic fungi at MIC range 3 x 10(-2) to 2.5 x 10(-1) mumol/mL, displayed cytotoxicity against KB cells ID50 in the range 2 x 10(-3) to 9 x 10(-3) mumol/mL, and stimulated the formation of calf thymus topoisomerase II mediated DNA cleavage at concentration between 0.4 and 10 microM. None of the indolo[2,3-b]quinolines belonging to the 6H series, i.e., lacking a methyl group on the pyridine nitrogen, was active in analogous tests. Of the investigated compounds, the most active was 2,5,9,11-tetramethyl-5H-indolo[2,3-b]quinoline, a compound bearing the highest number of symmetrically distributed methyl groups. The interaction of indolo[2,3-b]quinolines with DNA was studied by measuring the increase of calf thymus DNA denaturating temperature (Tm). The delta Tm values for the 5H series were found to be about 10 times as high as those for the 6H compounds. Indolo[2,3-b]quinolines with the highest number of methyl groups had the greatest contribution to the increase in the Tm of calf thymus DNA. The values of delta Tm reached 19 degrees C and 1.6 degrees C for the most substituted compounds of both series.
...
PMID:Synthesis and structure-activity relationship of methyl-substituted indolo[2,3-b]quinolines: novel cytotoxic, DNA topoisomerase II inhibitors. 793 79

The present study assessed the role of the p53 tumor suppressor gene in cell cycle arrest and apoptosis following treatment of Burkitt's lymphoma and lymphoblastoid cell lines with gamma-rays, etoposide, nitrogen mustard, and cisplatin. Cell cycle arrest was measured by flow cytometry; p53 and p21Waf1/Cip1 protein levels were measured by Western blotting; cell survival was measured in 72-96-h growth inhibition assays and by trypan blue staining, and apoptotic DNA fragmentation was assessed by either agarose gel electrophoresis or a modified filter elution method. We found that gamma-rays and etoposide induced a strong G1 arrest in the wild-type p53 lines while nitrogen mustard and cisplatin induced relatively little G1 arrest. All agents failed to induce G1 arrest in cells containing mutant p53 genes. The degree of G1 arrest observed with these agents correlated with the rate of p53 and p21Waf1/Cip1 protein accumulation: gamma-rays and etoposide induced rapid accumulation of both p53 and p21Waf1/Cip1; nitrogen mustard and cisplatin induced slow accumulation of p53 and no major accumulation of the p21Waf1/Cip1 protein. Despite differences in G1 arrest and kinetics of p53 or p21Waf1/Cip1 protein accumulation, all agents tended to decrease survival to a greater extent in the wild-type p53 lines compared to the mutant p53 lines. Cell death in the wild-type p53 lines was associated with intracellular DNA degradation into oligonucleosomal sized DNA fragments, indicative of apoptosis. We also observed an inverse sensitivity relationship between nitrogen mustard/cisplatin and etoposide in the mutant p53 lines and this was found to correlate with topoisomerase II mRNA levels in the cells. Our results suggest that p53 gene status is an important determinant of both radio- and chemosensitivity in lymphoid cell lines and that p53 mutations are often associated with decreased sensitivity to DNA damaging agents.
...
PMID:p53 gene mutations are associated with decreased sensitivity of human lymphoma cells to DNA damaging agents. 795 9

Using specific inhibitors we have assessed the role of topoisomerases I and II in DNA repair of the overall genome and in both strands of an essential gene, the dihydrofolate reductase (DHFR) gene in chinese hamster ovary (CHO) cells. In these studies we have: (1) used inhibitors of topoisomerases during the repair incubation and (2) studied the DNA repair in cells with altered levels of topoisomerase activity. When cells were allowed to repair after UV irradiation, the gene-specific DNA repair was not affected by either topoisomerase I or topoisomerase II inhibitors alone. However, when topoisomerase I and topoisomerase II inhibitors were added simultaneously the gene- and strand-specific DNA repair were markedly inhibited. In contrast, the overall genome DNA repair was only marginally affected. This suggests that topoisomerases are involved in gene-specific DNA repair and that one type may substitute for the other in the repair process. That concept is further supported by our findings using a mutant cell line with a decreased level of topoisomerase I: gene-specific DNA repair can be inhibited by a topoisomerase II inhibitor alone. By analyzing the steady-state expression of the DHFR gene we find that inhibition of repair in the DHFR gene is not ascribed to an obvious change in the messenger level. Furthermore, using agents other than UV, we observe that the inhibitors have no effect on gene-specific repair of DNA damage introduced by the chemotherapeutic agents cisplatin and nitrogen mustard.
...
PMID:Studies on the role of topoisomerases in general, gene- and strand-specific DNA repair. 840 8

Metastatic prostate cancer which is refractory to hormone therapy remains an incurable disease for which there is no effective therapy. We have begun to investigate the nuclear matrix, the RNA-protein network of the nucleus that plays an important role in DNA replication and gene expression, as a target for cancer chemotherapy. It was postulated that estramustine phosphate (EMP), an estradiol-nitrogen mustard conjugate that binds to the nuclear matrix, might enhance the cytotoxicity of etoposide (VP-16), a topoisomerase II inhibitor that acts at the level of the nuclear matrix. In a nascent DNA synthesis assay, EMP and etoposide interact to selectively inhibit new DNA synthesis on the nuclear matrix. In vitro, EMP and etoposide appeared to act synergistically to inhibit the growth of the metastatic Dunning rat prostate adenocarcinoma cell line Mat-LyLu as well as the metastatic human prostate adenocarcinoma cell line PC-3. In vivo, EMP and etoposide inhibited prostate adenocarcinoma growth in the Dunning Copenhagen rat model. These data have formed the basis of a Phase I/II clinical trial to examine the effect of EMP and etoposide in patients with stage D hormone-refractory prostate cancer.
...
PMID:Inhibition of prostate cancer growth by estramustine and etoposide: evidence for interaction at the nuclear matrix. 850 20

An array of novel 2-acyl-1,2-dihydroellipticines was prepared and evaluated for in vitro cytotoxicity in a variety of human cancer cell lines. The ellipticine analogs were also tested for inhibition of topoisomerase II in both decatenation and cleavable complex formation assays. Some of the new ellipticine derivatives were prepared by acylation of ellipticine with acid chlorides in tetrahydrofuran, followed by reduction of the intermediate 2-acylellipticinium ions with sodium cyanoborohydride. Others were synthesized by acylation of ellipticine with p-nitrophenyl chloroformate, reduction of the 2-acylellipticinium ion with sodium cyanoborohydride, and displacement of the p-nitrophenoxide anion with a variety of oxygen and nitrogen nucleophiles. The cytotoxicities of the new 2-acyl-1,2-dihydroellipticines varied widely, and correlated well with their topoisomerase II inhibitory activities.
...
PMID:Synthesis of a series of cytotoxic 2-acyl-1,2-dihydroellipticines which inhibit topoisomerase II. 867 54

A number of acridine derivatives, including the clinical antileukaemia agent amsacrine and the experimental agent DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide), target the enzyme topoisomerase II. We demonstrate here that DACA induces DNA cleavage in the presence of topoisomerase I as well as of topoisomerase II. We also investigate a series of acridine derivatives which link amsacrine to DACA in terms of DNA binding, topoisomerase poisoning and biological activity. The presence of an acridine 4-linked N-2-(dimethylamino)ethyl group provides both a pronounced G-C preference for DNA binding and activity towards topoisomerase I. The removal of the anilino side chain of amsacrine, in combination with the presence of the N-2-(dimethylamino)ethyl group, provides in vitro biological activity against "atypical" multidrug resistant leukaemia lines with low topoisomerase II activity. Among these compounds, suppression of the ionisation of the acridine nitrogen to produce the compound DACA is associated with experimental activity against solid tumours. The addition of an acridine 2-chloro substituent to DACA suppresses the stimulation of topoisomerase II-dependent DNA cleavage but increases stimulation of topoisomerase I cleavage. 2-Substitution also increases activity against the "atypical" multidrug resistant cell lines. Overall, the results suggest that augmentation of topoisomerase I-dependent activity in this series by appropriate chemical substitution in this series leads to circumvention of topoisomerase II-mediated multidrug resistance.
...
PMID:From amsacrine to DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide): selectivity for topoisomerases I and II among acridine derivatives. 869 77

A series of compounds structurally related to staurosporine, rebeccamycin, and corresponding aglycones was synthesized, and their activities toward protein kinase C and topoisomerases I and II were tested together with their in vitro antitumor efficiency against murine B16 melanoma and P388 leukemia cells. Their antimicrobial activities were also examined against a Gram-negative bacterium (Escherichia coli), a yeast (Candida albicans), and three Gram-positive bacteria (Bacillus cereus, Streptomyces chartreusis, and Streptomyces griseus). To avoid side effects expected with protein kinase C inhibitors, we introduced substitution on the maleimide nitrogen and/or a sugar moiety linked to one of the indole nitrogens to obtain specific inhibitors of topoisomerase I with minimal activities on protein kinase C. As expected, these structures were inefficient on topoisomerase II, and some of them exhibited a strong activity against topoisomerase I. Generally, dechlorinated compounds were found to be more active than chlorinated analogues against both purified topoisomerase I and protein kinase C. On the other hand, opposite results were obtained in the cell antiproliferative assays. These results suggest lack of cell membrane permeability in the absence of the chlorine residue or cleavage of carbon-chlorine bonds inside the cell.
...
PMID:Structure-activity relationships in a series of substituted indolocarbazoles: topoisomerase I and protein kinase C inhibition and antitumoral and antimicrobial properties. 889 41

The origin of cancer chemotherapy can be traced to the wartime discovery of the lymphotoxic action of nitrogen mustards. These and other bifunctional agents were later found to produce various types of DNA cross-links, and some of these agents continue to be mainstays of current therapy. The cellular pharmacology of these drugs was studied extensively during the 1970s and 1980s by means of DNA filter elution methodology. In the course of these investigations, DNA topoisomerases were discovered to be targets of anthracyclines and several other classes of anticancer drugs. DNA cross-linkers and topoisomerase blockers have generally similar cytotoxic mechanisms, which depend on DNA damage detection, DNA repair, cell cycle arrest, and cell death by apoptosis. The molecular control of these processes, involving oncogenes and tumor suppressor genes, is being revealed by current research. Cancer cells often have defects within these control systems, and these defects may confer selective sensitivity to appropriately designed drug therapy. Panels of human tumor cell lines may serve to link the molecular defects with specific drug sensitivities. Such correlations could guide the selection of drugs for therapy based on molecular diagnosis of individual tumors.
...
PMID:Beyond DNA cross-linking: history and prospects of DNA-targeted cancer treatment--fifteenth Bruce F. Cain Memorial Award Lecture. 897 Nov 50

We studied the role of DNA topoisomerase II in the biological actions of a series of novel alkylaminoanthraquinones, including N-oxide derivatives designed as prodrugs liable to bioreductive activation in hypoxic tumour cells. Drug structures were based upon the DNA-binding anticancer topoisomerase II poison mitoxantrone with modifications to the alkylamino side chains. The agents included AQ4, 1,4-bis{[2-(dimethylamino)ethyl] amino}5,8-dihydroxy-anthracene-9,10-dione, and AQ6, 1{[2-dimethylamino)-ethyl]amino}4-{[2[(hydroxyethyl)amino]ethyl]- amino}5,8-dihydroxy-anthracene-9,10-dione, together with the corresponding mono-N-oxide (AQ6NO) and di-N-oxide (AQ4NO). The R3N(+)-O- modification renders the terminal nitrogen group electrically neutral and was found to reduce AQ6NO or effectively abolish AQ4NO-DNA binding. Comparative studies were carried out using two SV40-transformed fibroblast cell lines, MRC5-V1 and AT5BIVA, the latter being a relative overproducer of DNA topoisomerase II alpha. The inhibition of DNA topoisomerase II decatenation activity ranked according to DNA-binding capacity. A similar ranking was found for drug-induced DNA-protein cross-linking in intact cells, depending upon topoisomerase II availability. Inhibition of DNA synthesis in S-phase synchronized cultures ranked in the order of AQ6 > mitoxantrone > > AQ6NO and was independent of topoisomerase II availability. Cytotoxicity of acute 1-h exposures for all agents except the inactive AQ4NO was enhanced in the topoisomerase II-overproducing cell line. The results indicate an important role for enzyme targeting in anthraquinone action. However, DNA synthesis inhibition and cytotoxicity were greater than expected for AQ6, given its topoisomerase- and DNA-interaction properties, and parallel studies have provided evidence of an additional role for enhanced subcellular accumulation and nuclear targeting. The inactivity of AQ4NO and the retention of only partial activity of AQ6NO, allied with the effective topoisomerase II-targeting and high cytotoxic potential of their presumed metabolites, favour their use as prodrugs in tumour cells with enhanced bioreductive potential.
...
PMID:DNA topoisomerase II-dependent cytotoxicity of alkylaminoanthraquinones and their N-oxides. 905 61

A Chinese hamster ovary cell line resistant to okadaic acid (OA), OAR2-3 has a mutation of the protein phosphatase (PP) 2A alpha gene and expresses a multi-drug resistance (MDR) phenotype. In the present work, we isolated two additional OA-resistant variants, also showing MDR with a cross-resistance profile similar to that of OAR2-3, and with increased and decreased expressions of the P-glycoprotein (Pgp) and DNA topoisomerase (topo) II protein, respectively. Unlike OAR2-3, however, they had no mutation in the same region of the PP2A alpha gene. Except for OA-resistance in OAR2-3, the MDR was found to decrease in the absence of OA, and this decrease was again associated with changes in topo II- and Pgp-expressions. Thus, we conclude that 1) OA regulates the expressions of Pgp and topo II positively and negatively, respectively, resulting in reversible expression of MDR irrespective of genetic changes and 2) in OAR2-3, the mutation in the PP2A alpha gene confers stable resistance to OA. The MDR was also linked with collateral sensitivity to some drugs, like cisplatin and nitrogen mustard.
...
PMID:Unstable expression of the multi-drug-resistant phenotype in Chinese hamster ovary cells resistant to okadaic acid. 912 89


<< Previous 1 2 3 4 5 6 7 8 Next >>

---