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)

Previously, we reported on the resistance to cis-diamminedichloroplatinum(II) (cis-DDP) of tumor cells in IgM immunocytoma tumors. In vitro cell lines were established, from tumors both sensitive and resistant to cis-DDP. The cultured cells obtained from the parent tumor were designated IgM-I, and those from a cis-DDP resistant tumor IgM/cDDP. In vitro dose response studies showed a difference in cis-DDP sensitivity with a resistance factor of approximately 20 at a relative survival of the tumor cells of 50 percent. The resistance factor was determined both in an assay with continuous cis-DDP exposure for 72 h, and in a clonogenic assay after an exposure for 1 h to various dosages of cis-DDP. The IgM/cDDP cells showed cross-resistance, in vitro and in vivo, to the currently used cis-DDP analogs carboplatin (CBDCA or JM8) and iproplatin (CHIP or JM9). Cross-resistance was also observed against the recently developed platinum(IV) compound tetraplatin. In addition, the cell line IgM/cDDP was resistant to other drugs interacting with DNA, such as doxorubicin (DXR), mitomycin C (MMC) and melphalan (L-PAM). For two non DNA-interacting drugs, vincristine (VCR), a mitosis inhibitor, and VP-16, a topoisomerase inhibitor, both cell lines were equally sensitive.
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PMID:Resistance of in vitro grown IgM immunocytoma cells to cis-diamminedichloroplatinum (II) (cis-DDP) and cross-resistance to other DNA interacting drugs. 234 18

The effects of various mutations in DNA-repair processes have been reported to either enhance or decrease bacterial sensitivity to cis-diamminedichloroplatinum(II) (cis-DDP). In the search for other mutations affecting bacterial sensitivity to this antitumor compound, we tested the E. coli B/r BS80 mutant, which is resistant to nalidixic acid (NalR). This mutation maps in the topoisomerase II gene (gyrA subunit) and leads to cross-resistance to cis-DDP. The mechanism underlying the resistance phenotype was only partly due to decreased DNA platination. BS80 was cross-resistant to mitomycin C and, to a lesser extent, to UV light, while it was normally sensitive to MNNG. The mechanisms involved in cis-DDP and mitomycin C resistance were independent of uvrA (excision repair) and recA (SOS repair and recombination) gene expression. In contrast, UV resistance was dependent upon recA gene expression. Both the reversion to NalS in BS80 and the transduction of NalR in the parental wild type (F26) did not modify cis-DDP toxicity; in addition, platinated plasmids equally survived in BS80 and F26 strains. Hence, it is possible that selection of the NalR phenotype induced other mutation(s) than gyrA responsible for cis-DDP, mitomycin C and UV resistance and/or that lesions with a different toxic potential were introduced by cis-DDP into the BS80 and F26 chromosomes.
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PMID:Resistance to cisplatin in an E. coli B/r NalR mutant. 768 61

By altering the accessibility of DNA sequences for alkylation or platination, and/or for subsequent repair, topoisomerase II can potentially affect the level of DNA interstrand cross-links induced in cells by bifunctional agents. In this study, we investigated the extent to which inhibition of topoisomerase II activity in a human glioblastoma multiforme cell line alters the kinetics of both the formation and the repair of total genomic DNA interstrand cross-links, as well as the sensitivity of the tumor cells to cis-diamminedichloroplatinum II (cis-DDP) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Cells were incubated with and without 200 microM novobiocin, a known topoisomerase II inhibitor, for 24 h, followed by exposure to 50 microM BCNU and 25 microM cis-DDP. DNA interstrand cross-linking was determined at various time points over 72 h, using a modified ethidium bromide-DNA binding assay. Sensitivity of the cells to cis-DDP and BCNU was also determined with and without novobiocin pretreatment with 200 microM novobiocin. This concentration of novobiocin showed no significant direct cytotoxicity, although it inhibited topoisomerase II activity in tumor cell nuclear extracts by 73%. A significant decrease in the rate of repair of both cis-DDP and BCNU induced DNA interstrand cross-links, with a corresponding decrease in the clonogenic survival of the cells, was observed following novobiocin exposure. Although the peak cross-link indices of novobiocin-treated cells relative to controls were not significantly increased, residual DNA cross-linking in the cells after 72 h was increased by 1.4-fold for BCNU and 3-fold for cells treated with cis-DDP, thus, indicating a greater effect of topoisomerase II on cross-link repair than on cross-link formation. These data suggest that inhibition of topoisomerase II may provide a potentially effective clinical strategy for sensitizing human brain tumors, and possibly other tumors as well, to DNA cross-linking anticancer agents.
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PMID:Topoisomerase II inhibition and altered kinetics of formation and repair of nitrosourea and cisplatin-induced DNA interstrand cross-links and cytotoxicity in human glioblastoma cells. 824 21

Clinical studies have suggested that both MDR1 and MRP may play a significant role in the chemosensitivity and outcome of neuroblastoma. To clarify the nature of multidrug resistance (MDR) in this tumour a series of six neuroblastoma cell lines have been characterized with regard to P-glycoprotein, MRP and LRP expression using immunocytochemistry and expression of MDR1, MRP, LRP and topoisomerase II genes using reverse transcription polymerase chain reaction (RT-PCR). By RT-PCR, all lines expressed MRP, five expressed LRP and four expressed MDR1, but protein levels of each of these were variable. Chemosensitization to a range of MDR-associated drugs (vincristine, doxorubicin, etoposide, taxotere, topotecan) and non-MDR-associated drugs (cisplatin, melphalan) by three modulating agents, cyclosporin A, PSC 833 and the novel Biricodar (VX-710; Incel), was evaluated using a colourimetric cytotoxicity assay (MTS). Alteration of daunorubicin efflux by these agents was evaluated using FACS analysis. Clonogenic assay was used to study the influence of these chemosensitizers on vincristine cytotoxicity. Marked sensitization to vincristine was observed in MDR1-positive lines, and a similar but less consistent effect was seen with taxotere, doxorubicin and etoposide. With MRP-positive, MDR-negative lines, only VX-710 caused consistent sensitization. These data confirm MDR1 and MRP expression as contributory factors in chemoresistance in neuroblastoma and indicate that VX-710 may be a useful modulator of both mechanisms and worthy of clinical evaluation in this tumour.
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PMID:BIRICODAR (VX-710; Incel): an effective chemosensitizer in neuroblastoma. 1037 71

Mouse erythroleukemia cells were treated with the topoisomerase II poison VP-16, the intrastrand crosslinking agent cis-DDP, and the ribonucleotide reductase inhibitor hydroxyurea. In all cases, the rate of DNA synthesis decreased as a result of the treatment. To study the mechanism of inhibition of DNA chain elongation, we determined DNA synthesis in a cell-free replication system containing isolated nuclei and cytoplasmic extracts. The rate of DNA synthesis in the reactions containing nuclei isolated from untreated cells and extracts from cells treated with the three drugs were slightly reduced and did not show significant differences between the drugs. In the systems containing nuclei from cells treated with cis-DDP, DNA synthesis was again slightly inhibited; synthesis in nuclei treated with hydroxyurea was enhanced, and synthesis in the systems containing nuclei from cells treated with VP-16 was significantly reduced. DNA synthesis was reduced to the same extent in a system containing nuclei isolated from untreated cells that had been briefly sonicated to introduce a limited number of double-strand breaks in the DNA. As VP-16 and sonication mediate changes in chromatin topology, these results suggest that, along with the trans-acting signal transduction pathways, there is a topologic mechanism for regulation of DNA synthesis in the S phase of the cell cycle.
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PMID:Regulation of DNA synthesis by the higher-order chromatin structure. 1085 95

The combination of cis-diamminedichloroplatinum (II) (DDP, cisplatin) and topoisomerase II inhibitor teniposide (VM-26) has been shown to exert a synergistic effect in the clinical treatment of cancer. In this study, the combined effect of DDP and VM-26 on the growth and induction of apoptosis in synchronized murine erythroleukemia (MEL) cells, treated at the beginning or in the middle of S-phase of cell cycle, was examined. MEL cells, clone F4 N, were synchronized by a double thymidine block leading to accumulation of 70% of cells at the G1/S boundary. The growth-inhibitory effect of DDP and VM-26 applied alone were stronger in the middle of the S-phase than at the beginning. Morphological analysis showed that the majority of the cells revealed typical signs of apoptosis: nuclei fragmentation and appearance of apoptotic bodies. The combination of both agents at low concentrations had a synergistic effect on cytotoxicity. At higher concentrations the effect was additive. The remainder of the cells were characterized by unbalanced growth, aberrant mitosis and appearance of multinucleated cells. These processes led to delayed cell death. The appearance of aberrant mitosis was more expressed after treatment in the middle of the S-phase. It is likely that as a result of the combined action of cisplatin and VM-26, cells become supersensitive to the ability of topoisomerase II inhibitor to influence mitosis, and this increased sensitivity may contribute to the observed synergism.
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PMID:Appearance of aberrant mitosis in murine leukemia cells upon combined treatment with low concentrations of cisplatin and teniposide. 1172 1

The inhibition of cell proliferation by 1,4-bis (1-naphthyl)-2,3-dinitro-1,3-butadiene (Naph-DNB) was evaluated in vitro against 4 cell lines (L1210/DDP, A2780/DX3, HCT-8/FU7dR, A549-T12) selected for their resistance to cisplatin, doxorubicin, 5-fluorouracil and taxol, and their wild-type counterparts. Naph-DNB is a novel anti-cancer compound obtained years ago within a research project of Organic Chemistry aimed at synthesizing 2,3-dinitrobutadiene derivatives. Because of its chemical structure, Naph-DNB was suggested to interact with nucleic acids, in particular DNA, and the other cellular macromolecules. This hypothesis made us consider Naph-DNB as a candidate for studies concerning its antitumour activity. We used the MTT assay to test the inhibition of cell proliferation after incubation of the cell lines with Naph-DNB for 72 h. For comparison, resistant and wild-type cell lines were also tested against those anticancer drugs used in vitro for their selection. In these culture conditions Naph-DNB retained its inhibiting activity against all resistant cells with IC50 values similar to those obtained in corresponding wild-type cell lines. Moreover, Naph-DNB was twice as effective as 5-fluorouracil against wild-type HCT-8 cells. Our previous findings about the interaction of Naph-DNB with DNA through the formation of interstrand cross-links suggested a mechanism of action similar to that of platinum/alkylating agents or topoisomerase inhibitors (intercalating agents). Our present data obtained by the K-SDS precipitation assay in A2780 and A549 cells showed that Naph-DNB is not able to form a stable topoisomerase-DNA complex as is the case for topoisomerase inhibitors. In conclusion, our results indicate that Naph-DNB is able to overcome some of the classical mechanisms of resistance selected by some anticancer drugs mainly used in clinical setting.
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PMID:1,4-Bis(1-naphthyl)-2,3-dinitro-1,3-butadiene a novel anticancer compound effective against tumor cell lines characterized by different mechanisms of resistance. 1520 65

A series of 3-substituted spiro[(dihydropyrazine-2,5-dione)-6,3'-(2',3'-dihydrothieno[2,3-b]naphtho-4',9'-dione)] derivatives were prepared using an easy synthetic route via condensation of the 3-amino-3-(ethoxycarbonyl)-2,3-dihydrothieno[2,3-b]naphtho-4,9-dione system and amino acids followed by intramolecular lactamization. Amino acids containing alkyl and aryl, linear and cyclic, polar and apolar, and basic and acid residues were incorporated. Evaluation of these analogues against the MCF-7 human breast carcinoma and SW 620 human colon carcinoma cell lines revealed, for the 3S,3'R isomers derived from Pro (7a), Cys (11a), and Met (12a) and the 3R,3'S isomer derived from D-Pro (7c), a cytotoxic potency comparable to or greater than that of doxorubicin. Some of these selected analogues were potent cytotoxic agents in several other sensible and resistant human solid tumor cell lines and may be able to circumvent the multiple-drug-resistance mechanism. In particular, only a partial cross-resistance to the compounds 7, 11, and 12 was observed in selected tumor cell sublines known to be resistant to doxorubicin (MCF-7/Dx and A2780/Dx), whereas a very low level of cross-resistance to compounds 7 and 11 was found in a tumor cell subline selected for resistance to cisplatin (A2780/DDP). In addition, the topoisomerase II inhibition activity and DNA-binding properties were investigated.
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PMID:Design, synthesis, and cytotoxic evaluation of a new series of 3-substituted spiro[(dihydropyrazine-2,5-dione)-6,3'-(2',3'-dihydrothieno[2,3-b]naphtho-4',9'-dione)] derivatives. 1737 2

Anthrapyrazoles are potent cytotoxic agents that intercalate into DNA, causing DNA strand breaks, inhibition of DNA synthesis and topoisomerase II. In this study, we investigated the in vitro cytotoxic activity of two anthrapyrazole analogues (AP-10 and AP-11) in human prostate (DU-145) and testicular (NTERA-2) carcinoma cells. The cytotoxic activity of these analogues was determined using the MTS cell growth inhibition assay. The IC50 of AP-10 on NTERA-2 and DU-145 cells was found to be 0.2 and 0.4 microM, respectively. AP-11 inhibited cell growth with an IC50 value of 1.2 microM (NTERA-2) and 3.2 microM (DU-145). Using trypan blue dye exclusion assay, we were able to confirm the cytotoxic effect of AP-10 and AP-11 on DU-145 cells, thereby distinguishing it from the cytostatic effect. To determine whether cells were able to recover after exposure to the anthrapyrazole analogues, DU-145 and NTERA-2 cells were exposed to the IC50 concentration of AP-10 and AP-11. After a 1-h exposure, fresh media containing either testosterone or dihydrotestosterone were added daily for five days and the cell growth rate was compared to the control. Although cells exposed to AP-10 and AP-11 were able to recover, they never attained the growth rate observed in the control cultures. The DNA fragmentation assay did not provide evidence of apoptosis. In conclusion, our results demonstrated that AP-10 had a higher cytotoxic activity than AP-11, and apoptosis appeared not to be involved in the biological activity of these compounds.
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PMID:In vitro cytotoxic activity of anthrapyrazole analogues in human prostate DU-145 and testicular NTERA-2 carcinoma cells. 1857 43

This study assessed the therapeutic effect of and adverse reactions to pirarubicin (THP) chemotherapy in osteosarcoma patients with lung metastasis, and analyzed the relationship between THP therapeutic effect and expression of p-glycoprotein and topoisomerase-II. Osteosarcoma patients with lung metastases at relapse were given THP and then cisplatin (DDP) or ifosfamide (IFO). Overall survival in patients receiving THP was 31.00 +/- 7.98 months, progression-free survival was 13.00 +/- 2.46 months. Objective response and partial response rates were 46.88% and 40.63%, respectively. There were no differences in overall survival and progression-free survival between the THP+DDP and THP+IFO regimens. Adverse reactions to THP chemotherapy were mainly gastrointestinal and myelosuppression. The therapeutic effect of THP was correlated with the abrogated expression of pglycoprotein and/or topoisomerase-II positive expression. For osteosarcoma patients with secondary lung metastasis, THP-based chemotherapy regimens are safe and effective as a salvage chemotherapy option.
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PMID:Therapeutic effect of pirarubicin-based chemotherapy for osteosarcoma patients with lung metastasis. 2043 72


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