Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PLC/PRF/5 hepatoma cells cultured with a tumor promoter teleocidin showed polygonal cellular appearance with many vacuole-like structures, and reduced both c-myc mRNA level and growth rate. These teleocidin effects were partly mimicked by sodium butyrate but not by a protein kinase C stimulant 1-oleoyl-2-acetylglycerol(OAG). Protein kinase C inhibitor 1-(5-isoquinolinyl-sulfonyl)-2-methyl-piperazine(H7), calmodulin-dependent protein kinase antagonist N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide(W7) and topoisomerase II inhibitor novobiocin failed to inhibit the effects of teleocidin. These results may suggest the presence of still unknown biochemical pathways which mediate the actions of teleocidin.
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PMID:Effects of teleocidin on the morphology and c-myc expression of hepatoma cells which are not inhibited by protein kinase antagonists. 310 17

The overall process of DNA biosynthesis can be divided into two major steps, one consisting essentially of nucleotide synthesis from low-molecular-weight metabolites and the other of polymerization of the nucleotides to form the duplicated DNA. Some antineoplastic agents are structural analogues of bases or nucleosides of intermediate metabolites, and are converted to their ribotides by enzymes catalyzing nucleotide metabolism. With some of these agents, the resulting ribotides then act as inhibitors of nucleotide synthesis. With others the resulting ribotides are subjected to stepwise enzymatic reactions and are then incorporated into DNA during its synthesis, thus rendering it inactive. Some antineoplastic agents, on the other hand, affect the DNA chain apparently through intercalation in double-stranded DNA, binding to DNA or nuclear protein, or interstrand linkage, or else through activation of endonuclease or inhibition of topoisomerase. The former effects result in inhibition of DNA double-strand dissociation, while the latter result in double-stranded DNA scission and apurinic acid formation. Antineoplastic agents thus vary widely, with respect to both the processes of their activation and inactivation and their effects on DNA synthesis. Their mechanisms of action and effects also tend to differ among various types of tumor cells and host organs. Investigation of the action mechanisms of these agents and determination of their appropriate utilization will be required in order to achieve better results in cancer chemotherapy.
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PMID:[Mechanism of action of antineoplastic agents in the DNA synthesis of tumor cells]. 329 63

The effects of various antileukemic agents on DNA replication associated with the nuclear matrix were investigated in CCRF-CEM leukemia cells. Residual nuclear matrices were prepared by sequential treatment of nuclei with 1.5 M NaCl, DNase I, and Triton X-100 and contained 1-5, 10, and 37% of the total nuclear DNA, protein, and phospholipid, respectively. In control cells pulse-labeled for 45 s with [3H]thymidine, the specific activity of nascent DNA was four-fold greater in the nuclear matrix fraction relative to the specific activity of the high salt-soluble (nonmatrix) DNA fraction. Pulse-labeling and reconstitution experiments indicated that this enrichment of newly replicated DNA on the nuclear matrix did not result from aggregation of nascent DNA with the matrix. A 2-h incubation of tumor cells with either 0.1 microM teniposide (VM-26), 0.2 microM VM-26, or 0.5 microM amsacrine (m-AMSA) reduced the relative specific activity of nascent DNA on the nuclear matrix by 59, 61, and 54%, respectively, compared to control cells. In contrast hydroxyurea and cytosine arabinoside, at concentrations that markedly inhibited total nuclear DNA synthesis, did not decrease the relative specific activity of newly replicated DNA on the matrix. The results provide evidence that the antiproliferative effects of the DNA topoisomerase II inhibitors, VM-26 and m-AMSA, are localized on the nuclear matrix of CCRF-CEM leukemia cells.
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PMID:Effects of antileukemia agents on nuclear matrix-bound DNA replication in CCRF-CEM leukemia cells. 334 63

Recent developments in the molecular genetics of human cancers shows the importance of multiple genetic alterations in the pathogenesis of these lesions. DNA diagnostic techniques are being introduced rapidly into the clinical laboratory setting. 1) In lung cancer, several oncogenes and tumor suppressor genes, such as ras, myc, p53, RB, allelic loss of chromosomes, play very important roles. These genetic changes are being applied to cancer diagnosis, prediction of prognosis or disease metastasis, or response to treatment. 2) Drug resistance is one of the major problems of current lung cancer chemotherapy. Identification of the molecular marker for drug resistance, like DNA topoisomerase gene mutation, in clinical samples will be of great help for choosing chemotherapy regimens. 3) Interindividual differences in susceptibility to lung cancer may be screened using genotyping of the P450IA1 and GSTmu genes. To develop newer diagnostic and therapeutic approaches, detailed investigation of the molecular pathogenesis of lung cancer using clinical samples is essential. I review the present status on these applications of genetic markers to lung cancer diagnosis in this article.
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PMID:[Application of molecular diagnosis to human lung cancer]. 747 38

The relationship between topoisomerase II activity and ribosomal RNA synthesis was investigated using the antitumoral drug VM26, a specific inhibitor of topoisomerase II. For this purpose TG cells, a human tumor cell line, were cultured in the presence of 2.5 microM VM26 for 1 and 3 h; VM26 reduced the topoisomerase II activity, measured in whole cell extracts. In the presence of VM26 the [3H]uridine incorporation into ribosomal RNA was decreased; electron microscopy investigation of nucleoli showed a segregation of nucleolar components. Because VM26 stabilizes the cleavable complex and inhibits the resealing reaction, thus causing potential cleavage sites, we have analyzed the double-strand breaks caused by the drug treatment in the tandem repeat ribosomal DNA (rDNA) genes, by indirect labeling with two probes recognizing the 5' portion of ETS (BES) and the 3' portion of 28S (LS6BE) transcribed gene. In VM26-treated cells rDNA is fragmented and a topoisomerase II preferential cleavage site is present, localized at 1.85 kb in 28S region from 3' EcoRI site.
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PMID:Inhibition of topoisomerase II activity and its effect on nucleolar structure and function. 751 Feb 50

Tumor cell resistance to cytotoxic drugs is considered one of the major obstacles to successful chemotherapy. Multidrug resistance (MDR) describes the simultaneous expression of cellular resistance to a wide range of structurally and functionally unrelated drugs. The development of the multidrug resistance phenotype is accompanied by multiple morphological and biochemical changes: (a) increased glutathione levels in the cytoplasm, (b) modified levels of enzymes in the nucleus, particularly topoisomerase II, (c) increased DNA repair capacity and (d) overexpression of the (human) MDR1 gene encoding a transmembrane efflux pump (P-glycoprotein, gp-170), which leads to decreased intracellular accumulation and therefore to resistance to a variety of cytotoxic drugs. In this report we describe a competitive polymerase chain reaction (PCR) assay for the absolute quantification of MDR1 mRNA. This assay uses a transcript generated in vitro as an internal standard which is later coamplified together with the MDR1 cDNA. Both cDNAs exhibit the same MDR1 primer sites but differ in the length of the amplicon. For a second round of amplification we applied nested MDR1 primers and were successful in improving the sensitivity of this competitive PCR system. This test for characterizing the MDR1 expression offers high sensitivity and specificity and is therefore of great clinical relevance. It should be useful in improving monitoring and design of chemotherapy.
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PMID:Competitive nested polymerase chain reaction for quantification of human MDR1 gene expression. 751 88

Drugs that interact with DNA topoisomerases I and II hold great promise for the treatment of cancer, however, like many other anti-cancer agents, they are a double-edged sword and may themselves cause mutation and cancer. In vitro studies show that clinically effective agents, such as etoposide, doxorubicin and others, stabilize a ternary complex where topoisomerase II is covalently linked to DNA. This complex represents an intermediate in the topoisomerase-II catalyzed DNA supercoil relaxation reaction. Camptothecin and its analogues stabilize a similar ternary complex, in vitro, consisting of topoisomerase I covalently linked to DNA at single-strand breaks. Short-term tests of genotoxicity confirm that topoisomerase-interactive agents are mutagenic and suggest common mechanisms by which they induce mutation and selectively kill tumor cells. These agents induce sister-chromatid exchange, chromosomal aberrations and mutations in specific mammalian genes. Their propensity to induce small colonies in the L5178/TK+/(-)-3.7.2C assay implies that topoisomerase-interactive agents induce large DNA rearrangements and deletions. These may result from topoisomerase-subunit exchange at drug-stabilized ternary complexes or from attempts by the cell to bypass the replication block caused by stabilized ternary complexes. Studies in bacterial mutation assays suggest that topoisomerase-interactive agents may also induce mutations, albeit at a lower rate, through simple DNA intercalation or via generation of oxygen free radicals. Second malignancies observed in patients previously treated with topoisomerase II interactive agents suggest these may be an important clinical consequence of their capacity to induce mutation. In particular, a unique form of acute myelogenous leukemia is observed at strikingly high frequencies after treatment with relatively high doses of the epipodophyllotoxins etoposide and teniposide. This form of AML has been reported after the uses of other classes of topoisomerase-interactive agents as well. Cancer induction is therefore a toxic consequence predicted by short-term tests of genotoxicity and should be weighed against the potential therapeutic benefits of topoisomerase-interactive agents.
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PMID:International Commission for Protection Against Environmental Mutagens and Carcinogens. Mutagenicity and carcinogenicity of topoisomerase-interactive agents. 751 27

Several new pyridoacridine alkaloids, dehydrokuanoniamine B (1), shermilamine C (2), and cystodytin J (3), in addition to the known compounds cystodytin A (4), kuanoniamine D (5), shermilamine B (6), and eilatin (7), were isolated from a Fijian Cystodytes sp. ascidian. Their structures were determined by analyses of spectroscopic data. These compounds along with a previously reported pyridoacridine, diplamine (8), showed dose-dependent inhibition of proliferation in human colon tumor (HCT) cells in vitro. All compounds inhibited the topoisomerase (TOPO) II-mediated decatenation of kinetoplast DNA (kDNA) in a dose-dependent manner. The pyridoacridines' ability to inhibit TOPO II-mediated decatenation of kDNA correlated with their cytotoxic potencies and their ability to intercalate into calf thymus DNA. These results suggest that disruption of the function of TOPO II, subsequent to intercalation, is a probable mechanism by which pyridoacridines inhibit the proliferation of HCT cells. Incorporation studies show that pyridoacridines disrupt DNA and RNA synthesis with little effect on protein synthesis. It appears that DNA is the primary cellular target of the pyridoacridine alkaloids. These results are consistent with those for known DNA intercalators.
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PMID:Inhibition of topoisomerase II catalytic activity by pyridoacridine alkaloids from a Cystodytes sp. ascidian: a mechanism for the apparent intercalator-induced inhibition of topoisomerase II. 752 59

Four second-generation Illudin analogues were synthesized and tested for antitumor activity using a metastatic lung carcinoma xenograft model resistant to conventional antitumor agents. One analogue, the parent illudofulvene-derivative called Acylfulvene, inhibited xenograft primary tumor growth and prolonged life span of tumor-bearing animals when administered i.p. or i.v. The efficacy of Acylfulvene exceeded that of mitomycin C, cisplatin, paclitaxol, the parent compound Illudin S, and an earlier analogue, dehydroilludin M. Promising features of this new analogue are: (a) the retention of in vitro activity against a variety of mdr tumor phenotypes including gp170+, gp150+, GSHTR-Pi, topoisomerase I, and topoisomerase II mutants; and (b) an apparent selective cytotoxicity toward cells deficient in either ERCC2 or ERCC3 DNA helicase activity.
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PMID:Efficacy of Acylfulvene Illudin analogues against a metastatic lung carcinoma MV522 xenograft nonresponsive to traditional anticancer agents: retention of activity against various mdr phenotypes and unusual cytotoxicity against ERCC2 and ERCC3 DNA helicase-deficient cells. 758 33

Tumor tissues of untreated and cytostatic-agent-treated patients with nephroblastomas were investigated for expression of resistance-related proteins (P-glycoprotein, glutathione S-transferase-pi, glutathione peroxidase and topoisomerase II) to ascertain whether resistance proteins are changed after treatment. Tumor tissue was analyzed by means of mRNA. Twenty-three children were treated with actinomycin D and vincristine for 4 to 8 weeks. Eight children received no preoperative chemotherapy. In untreated patients, no expression of P-glycoprotein was seen, whereas, in the patients who were treated with actinomycin D and vincristine, 12 out of 23 tumors showed increased P-glycoprotein expression (> mean value). Although we found no difference between treated and untreated tumors for glutathione S-transferase-pi, we found significant differences in the expression of glutathione peroxidase. In the 8 untreated patients, 7 tumors showed low glutathione peroxidase (< mean value) and one high (> mean value) glutathione-peroxidase-mRNA content. With treatment, 11 tumors expressed low levels and 12 tumors high levels of mRNA. A significant positive correlation between P-glycoprotein and glutathione peroxidase was found. In addition, of the 8 untreated patients, 2 had low topoisomerase-II expression, and 6 high expression. With treatment, the expression was reduced in 18 tumors, and only 5 tumors had high levels of this protein. These results were confirmed by PCR and immunohistochemistry.
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PMID:Expression of resistance-related proteins in nephroblastoma after chemotherapy. 759 Dec 3


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