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:5.99.1.3 (topoisomerase)
9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inherited susceptibility to a wide variety of neoplasias (Li-Fraumeni syndrome), has been shown in studies of one cancer-prone family, to have an intriguing association with an aberrant c-raf-1 gene and inheritance of a radioresistant phenotype in their non-cancerous skin fibroblasts. This association together with observations that DNA topoisomerases, when defective, can introduce errors into DNA and that these enzymes are perturbed in vitro by serine/threonine kinases similar to raf encoded proteins, prompted investigation of DNA topoisomerase activity of the family's fibroblasts. Since radioresistance was transferred to murine cells (NIH-3T3) when the aberrant c-raf-1 gene from this family was transfected, we also examined transformants containing this and other oncogenes. V-raf/c-myc and EJ-ras transformants were examined, the former because the family's skin fibroblasts also have 3-8-fold elevated myc expression (not apparently relevant to radioresistance) and the latter because ras, like raf, conveys radioresistance. The family members' fibroblasts and the three transfected murine lines, showed a similar perturbation of a spermidine and ATP-dependent DNA catenation activity (typical of DNA topoisomerase II). There was a significant positive correlation (r = 0.93; P = 0.0026) between the degree of activation of topoisomerase II and one measure of radioresistance (the Dq value). Relaxation of DNA supercoiling (topoisomerase I activity and other DNA nicking enzymes) was not abnormal. Cytotoxicity assays and evaluation of the influence of topoisomerase II inhibitors on DNA/protein complex formation, corroborated the existence of a qualitative topoisomerase II defect in the family's cells and transfectants. Although the contention that the qualitative topoisomerase II abnormalities observed here may be associated with malfunction is highly speculative, these findings may be relevant to the mechanism of oncogenesis, not only in this family, but with raf and ras type oncogenes.
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PMID:Aberrant DNA topoisomerase II activity, radioresistance and inherited susceptibility to cancer. 184 52

A case of therapy-related acute non-lymphocytic leukemia (t-ANLL) in a 70-year-old female patient is reported. An operation for lung cancer was performed in February 1991, and she was treated with etoposide (VP-16), a topoisomerase II inhibitor. Nineteen months after the start of chemotherapy, she complained of palpitations, and anemia and thrombocytopenia developed. The myelogram revealed 41.2% leukemic cells, and a diagnosis of t-ANLL induced by VP-16 was made. The karyotype of bone marrow cells showed 46, XX, t(7;11) (p13;p15), 16p+. She obtained complete remission (CR) by treatment with low dose cytosine arabinoside (Ara-C) and cytarabine ocfosfate (SPAC). Karyotype with t-ANLL induced by alkylate agents frequently shows unbalanced abnormalities. The difference of cytogenetic findings suggest the difference of mechanisms. Detailed chromosomal analysis make clear the oncogenesis of t-ANLL. It is reported that the prognosis of patients with t-ANLL treated by conventional chemotherapy is poor. Considering that elderly cases of acute leukemia have a lower probability of achieving CR than non-elderly cases, because of complications and side effects of chemotherapy such as bone marrow suppression, treatment with low dose Ara-C and SPAC is thought to be indicated in elderly patients with t-ANLL.
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PMID:[Therapy-related acute non-lymphocytic leukemia (M2) with 7;11 chromosome translocation induced into complete remission by low dose cytosine arabinoside and cytarabine ocfosfate therapy]. 807 12

DNA methylation is deregulated during oncogenesis. Since several major anti-cancer drugs act on topoisomerases, we investigated the effects of cytosine methylation on topoisomerase cleavage activities. Both topoisomerase I and II cleavage patterns were modified by CpG methylation in c-myc gene DNA fragments. Topoisomerase II changes, mainly cleavage reduction, occurred for methylation sites within 7 base pairs from the topoisomerase II breaks and were different for VM-26 and azatoxin. For topoisomerase I, cleavage enhancement as well as suppression were observed. Using synthetic methylated oligonucleotides, we show that hemimethylation is sufficient to alter topoisomerase I activity. Cytosine methylation on the scissile strand within the topoisomerase I consensus sequence had strong effects. Cleavage was stimulated by methylation at position -4 and was strongly inhibited by methylation at position -3 (with position -1 being the enzyme-linked nucleotide). This inhibitory effect was attributed to the presence of a methyl group in the major groove, since the transition uracil to thymine also inhibited cleavage. Altogether these results suggest an interaction of topoisomerase I with the DNA major grove at positions -3 and -4. In addition, DNA methylation may have profound effects on the activity of topoisomerases and may alter the distribution of cleavage sites produced by anticancer drugs in chromatin.
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PMID:Effects of DNA methylation on topoisomerase I and II cleavage activities. 813 7

The National Cancer Institute (NCI) recently alerted clinicians to the possibility that patients, entered on a NCI-sponsored cooperative group trial of doxorubicin and cyclophosphamide adjuvant therapy for breast cancer, may be at high risk of developing secondary acute myeloid leukemia (AML). Secondary AML following standard doses of doxorubicin and cyclophosphamide is uncommon, suggesting that the high risk on this trial may result from its higher-than-standard doses of chemotherapy. However, the cases of secondary AML were characteristic of the type that follows treatment with topoisomerase II-active agents, especially etoposide, and this type of secondary AML is rare after treatment with either cyclophosphamide or doxorubicin at any dose. We raise the possibility that another component of this trial, hematopoietic growth factors to decrease the toxicities related to myelosuppression, may play an important role in the development of secondary AML. Growth factors not only stimulate hematopoietic progenitor proliferation and differentiation, they also regulate hematopoietic cell survival by interfering with apoptosis (programmed cell death). Inhibition of apoptosis by a variety of genetic factors is an important mechanism of oncogenesis, and appears to be the initiating event in some malignancies. Growth factor-mediated suppression of the apoptotic death of hematopoietic progenitors damaged by chemotherapy may contribute to their leukemic transformation.
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PMID:Are growth factors leukemogenic? 855 25

Populations of tetraploid cells are found in a variety of human tumours where they may act as precursors of aneuploidy and tumorigenesis. Here we demonstrate the drug induction of tetraploid cells at mitosis by interference with cell cycle checkpoints and the coordination of mitotic events. Tetraploid cells result from mitotic exit in the absence of either chromosome segregation or cytokinesis. One class of agents that induces tetraploidy causes override of cell cycle checkpoints that require metaphase chromosome alignment as a pre-condition for initiating exit from mitosis. As a result cells exposed to such drugs progress partially through mitosis, but exit without chromosome segregation or cytokinesis. Inhibitors of microtubule assembly comprise a second class of agents that induce tetraploidy. Many cell types are incapable of maintaining indefinite mitotic arrest in the presence of microtubule inhibitors and finally exit mitosis without microtubule dependent chromosome segregation. Inhibitors of topoisomerase II represent a third class of drugs that induce tetraploidy at mitosis. By inhibiting DNA decatenation required for sister chromatid separation at the onset of anaphase such drugs block chromosome segregation. When topoisomerase II activity is inhibited, cells nonetheless reform nuclei and exit from mitosis without chromosome segregation. Finally, inhibition of cleavage furrow formation by agents such as cytochalasins represents a fourth mechanism of tetraploidization at mitosis. We find that when Chinese Hamster Ovary cells become tetraploid, regardless of which mechanism induces this state, they are genetically unstable and become aneuploid at the subsequent mitosis. In conclusion, the failure of mitotic checkpoint function can generate gross aneuploidy from which cells with an advantage for tumor growth may be selected.
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PMID:Chemical induction of mitotic checkpoint override in mammalian cells results in aneuploidy following a transient tetraploid state. 901 37

Soy-based diets, rich in the isoflavones genistein and daidzein, are thought to protect against breast and prostate cancer. We used the N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis animal model to test the effectiveness of these two isoflavones as chemopreventive agents. Each isoflavone was injected daily into 35-day-old rats for six months while we monitored the animals' body weight and mammary tumor appearance. Genistein was effective in reducing tumor multiplicity, but it reduced tumor incidence only marginally. Daidzein was less effective in reducing both tumor incidence and multiplicity. To investigate genistein's mechanism of action, we determined the topoisomerase II (topo II) activity and detected the phosphotyrosine-containing peptides in the extracts of mammary tissues isolated from control and isoflavone-treated animals. Mammary tumors contained over 60-fold higher topo II enzymatic activity than the mammary glands. Similarly, more tyrosine phosphopeptides were detectable in mammary tumors than in mammary glands. Tissue samples from genistein treated animals contained similar topo II and protein tyrosine kinase (PTK) activities as the control group. These data suggest that mammary tumorigenesis is accompanied by an extensive increase in topo II and PTK activities. The mechanism of chemoprevention by genistein, however, is independent of topo II or PTK inhibition.
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PMID:Inhibition of N-methyl-N-nitrosourea-induced mammary tumors in rats by the soybean isoflavones. 904 3

Loss of DNA mismatch repair (MMR) has been observed in a variety of human cancers. In addition to predisposing to oncogenesis, loss of MMR activity is of concern with respect to the use of chemotherapeutic agents to treat established tumors. Loss of MMR results in drug resistance directly by impairing the ability of the cell to detect DNA damage and activate apoptosis and indirectly by increasing the mutation rate throughout the genome. The MMR proteins are involved in mediating the activation of cell cycle checkpoints and apoptosis in response to DNA damage. MMR-deficient cells have been reported to be resistant to the methylating agents procarbazine and temozolomide, the alkylating agent busulfan, the platinum-containing drugs cisplatin and carboplatin, the antimetabolite 6-thioguanine, and the topoisomerase II inhibitors etoposide and doxorubicin. In the case of cisplatin, busulfan, temozolomide, and procarbazine, the degree of resistance has been shown to be sufficient to produce a large difference in clinical responsiveness in vivo in tumor model systems. The available preclinical data suggest that tumors that contain a significant fraction of cells deficient in MMR will demonstrate reduced responsiveness to specific drugs. The challenge now is to assess the clinical significance of the presence of deficient cells in tumors and to discover drugs that retain activity against MMR-deficient cells.
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PMID:The role of DNA mismatch repair in drug resistance. 951 45

Scaffold or matrix attachment regions (S/MARs) are noncoding genomic DNA sequences displaying in vitro selective binding affinity for nuclear scaffold. They have been reported to be involved in the physical attachment of genomic DNA to the nuclear scaffold, and thus in the organization of the chromatin in functional loops or domains, and in the regulation of gene expression. In this work, we report the identification of an S/MAR in a woodchuck chromosomal locus, named b3n, previously described as a recurrent site of woodchuck hepatitis virus (WHV) DNA integration in woodchuck hepatocellular carcinoma (HCC). The 4.3-kb sequence of this locus contains several Alu-like repeats and a gag-like coding region with frameshift mutations. Computer analysis revealed the presence of a region with unusually high AT content, typical of most S/MARs, and of specific motifs (A boxes, T boxes, topoisomerase II sites, and unwinding elements) overlapping or in proximity to the region with high AT content, predicting that b3n might contain an S/MAR. Fragments of the b3n locus were isolated by conventional and inverse PCR techniques. In in vitro binding experiments with both heterologous and autologous scaffold preparations, a 592-bp fragment spanning the region rich in S/MAR features showed marked scaffold affinity, which was specific when autologous scaffolds were used. The presence of an S/MAR at the b3n locus and its nature as a recurrent WHV integration site in HCC suggest the involvement of S/MAR elements in some of the mechanisms leading to liver oncogenesis.
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PMID:Identification of scaffold/matrix attachment region in recurrent site of woodchuck hepatitis virus integration. 965 45

A patient with chronic hepatitis associated with hepatitis C virus infection was observed to convert from antinuclear antibody-negative to antinuclear antibody-positive status at the time when liver cancer was detected. The newly recognized antibodies reacted with a nuclear protein doublet of 170 and 180 kDa in immunoblotting, and in fluorescence-activated flow cytometry the antigens were shown to vary in expression level in a cell cycle-related manner: minimum in G1, increasing in S, and maximum in G2 and M. In synchronized HeLa and HEp-2 cells, immunofluorescence microscopy showed uniformly distributed staining of the nucleoplasm in S-phase, with increased intensity of nucleoplasmic staining in G2, at which time nucleolar staining was also present. In M, condensed chromosomes were uniformly stained. Using previously characterized polyclonal antibodies to DNA topoisomerase II (topo II) as reference markers, the antigens recognized by the patient's serum were shown in Western blotting to have the same mobilities as DNA topo IIalpha (170 kDa) and beta (180 kDa) isoforms. The patient's serum was also highly efficient in inhibiting DNA topo II in an in vitro functional assay. Antibody to DNA topo II appeared de novo in close association with transformation to cancer, and since dysregulation of DNA topo II is considered to be involved in some forms of tumorigenesis, the observed antibody response in this patient could conceivably be an immune reaction to the abnormally regulated protein.
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PMID:Autoantibody to DNA topoisomerase II in primary liver cancer 981 99

Somatic changes in CpG dinucleotide methylation occur quite commonly in human cancer cell DNA. Relative to DNA from normal human colonic cells, DNA from human colorectal cancer cells typically displays regional CpG dinucleotide hypermethylation amid global CpG dinucleotide hypomethylation. The role of the maintenance DNA methyltransferase (DNMT1) in the acquisition of such abnormal CpG dinucleotide methylation changes in colorectal cancer cells remains controversial; in one study, 60-200-fold increases in DNMT1 mRNA expression were detected in colorectal polyps and cancers relative to normal colonic tissue [W. S. El-Deiry et al., Proc. Natl. Acad. Sci. USA, 88: 3470-3474, 1991], whereas in another study, only small increases in DNMT1 mRNA expression, commensurate with differences in cell proliferation accompanying colonic tumorigenesis, were observed [P. J. Lee et al., Proc. Natl. Acad. Sci. USA, 93: 10366-10370, 1996]. To definitively ascertain whether abnormal DNMT1 expression might accompany human colorectal carcinogenesis, we subjected a series of normal and neoplastic colonic tissues to immunohistochemical staining using a polyclonal antiserum raised against a DNMT1 polypeptide. A concordance of DNMT1 expression with the expression of PCNA and other cell proliferation markers, such as Ki-67 and DNA topoisomerase IIalpha, was observed in normal colonic epithelial cells and in cells comprising other normal epithelia and lymphoid tissues. The polypeptide p21, which has been reported to undermine DNMT1 binding to proliferating cell nuclear antigen at DNA replication sites, was not expressed by normal colonic cells containing DNMT1 and other cell proliferation markers. In adenomatous polyps, although DNMT1 expression coincided with the expression of other cell proliferation markers, many DNMT1-expressing cells also expressed p21. The fidelity of DNMT1 expression was further undermined in colorectal carcinomas, in which a striking heterogeneity in DNMT1 expression, with some carcinoma cells containing very high DNMT1 levels and others containing very low DNMT1 levels, was observed. These results indicate that human colorectal carcinogenesis is accompanied by a progressive dysregulation of DNMT1 expression and suggest that abnormalities in DNMT1 expression may contribute to the abnormal CpG dinucleotide methylation changes characteristic of human colorectal carcinoma cell DNA.
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PMID:Abnormal regulation of DNA methyltransferase expression during colorectal carcinogenesis. 1046 69


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