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)

Chronic lymphocytic leukemia lymphocytes were used to study mechanisms involved in apoptosis (programmed cell death). Apoptosis, which was determined by morphological changes including cell death and by internucleosomal DNA fragmentation, occurred during culture for 1 to 2 days in a portion of the cells from three of the four patients tested. Most of the cells underwent apoptosis and DNA fragmentation was greatly enhanced when cells were cultured in the presence of the microtubule inhibitor colchicine, the topoisomerase II inhibitor etoposide, or the glucocorticoid methylprednisolone. Tumor-promoting phorbol esters inhibited spontaneous DNA fragmentation and cell death including that induced by colchicine, etoposide, and methylprednisolone, indicating that they act on an event common to apoptosis caused by diverse stimuli. Phorbol esters probably act through protein phosphorylation, since they were effective at concentrations which modulated protein kinase C (PKC) and their action was prevented by H-7, which binds to and inactivates the catalytic site of PKC. In the absence of phorbol ester, H-7 itself induced some apoptosis. These findings implicate PKC in the suppression of apoptosis, but its precise role requires systematic investigation.
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PMID:Induction of apoptosis in chronic lymphocytic leukemia cells and its prevention by phorbol ester. 172 40

The stabilization of the cleavable complex between DNA topoisomerase II and DNA by adriamycin (ADR), as well as by other topoisomerase II-targeted drugs, is an essential step in a process associated with drug cytotoxicity. Unlike many other cell types, ADR does not produce DNA cleavage in the lymphocytes of chronic lymphocytic leukemia (CLL). The CLL lymphocytes have been identified as quiescent cells with an extremely low level of topoisomerase II. The low level of this enzyme could constitute a basis for a new mechanism of drug resistance operating not only in CLL, but perhaps in any slow growing cancer with a large population of quiescent cells. Other factors contributing to drug resistance could include changes in enzyme regulation or processing of the cleavable complex, or the presence of a "mutant" enzyme which renders cancer cells unresponsive to topoisomerase II-targeted drugs. Suggested strategies in drug development, aimed at the topoisomerase II-related drug resistance, could include 1) the selection of topoisomerase I as an alternative target for cancer chemotherapy, 2) the development of ADR analogs which, unlike ADR, stabilize the topoisomerase II-DNA complex with high efficiency, and 3) the search for agents enhancing the SOS-like repair response, presumably triggered by DNA topoisomerase-targeted drugs.
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PMID:DNA topoisomerase II as a potential factor in drug resistance of human malignancies. 304 Dec 36

Chronic lymphocytic leukaemia (CLL) is a progressive disease, commonly treated in its early stage with alkylating agents. A multi-agent regimen which includes anthracyclines is used to treat advanced disease. Despite chemotherapy, the disease remains incurable. There is now considerable evidence to suggest that anthracyclines exert their effect via the nuclear enzyme topoisomerase II and that alterations in amount or activity of this enzyme may mediate drug resistance. We have investigated topoisomerase II mRNA expression in 34 CLL patients and in haemopoietic cells from 10 normal donors. Expression was found to be low but detectable in all patients and normals. Such low levels may contribute to the toxicity of alkylating agents, but could severely limit the effect of anthracyclines.
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PMID:Topoisomerase II expression in normal haemopoietic cells and chronic lymphocytic leukaemia: drug sensitivity or resistance? 839 82

Gene expression was analyzed by cDNA-PCR at the mRNA level in bone marrow samples (>80% blasts) from ALL (28 primary, 22 first relapses, 10 recurrent relapses), from AML (14 primary, 23 relapses), In peripheral blood lymphocytes from CLL (five untreated, 10 treated), in one CML in blast crisis in the course of the disease (four samples), and in bone marrow samples from healthy donors (12 specimens). We found low mean MDR1 expression in primary ALL, first relapses of ALL, and primary AML. Significantly higher mean relative MDR1 expression levels were seen in recurrent relapses of ALL, and in the group of relapsed state AML. MDR1 expression measured intermediate in bone marrow samples from healthy donors. The CLL lymphocytes showed generally relatively high MDR1 expression levels. MRP gene expression measured very similar in primary ALL, first relapses of ALL, primary AML, and normal bone marrow. Significantly increased MRP mRNA levels were observed in the groups of recurrent ALL and relapsed state AML. CLL lymphocytes also showed high MRP expression levels. A combined increase of MDRI (about 20-fold) and MRP (about four-fold) was monitored in samples obtained from the CML in blast crisis after chemotherapy. While no significant differences of the mean topoisomerase IIbeta mRNA levels were found throughout, a significantly decreased topoisomerase IIalpha gene expression was measured in first and recurrent relapses of ALL. In CLL lymphocytes either the expression of the topoisomerase IIalpha gene was not detectable by cDNA-PCR, or it measured very low. Topoisomerase IIalpha gene expression was correlated to cyclin A gene expression in the samples of acute leukemias, Indicating the link of topoisomerase IIalpha expression to the proliferative activity of these leukemic blast cells. Our results point to a potentially multifactorial emergence of multidrug resistance in particular states and types of leukemias.
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PMID:MDR1, MRP, topoisomerase IIalpha/beta, and cyclin A gene expression in acute and chronic leukemias. 865 99

Peripheral blood samples from 18 patients with chronic lymphocytic leukemias (CLL) who were either untreated but who were later sensitive to chlorambucil (CLL S) or resistant to a combination containing doxorubicin, vincristine, cyclophosphamide and prednisone (CLL R) were studied for glutathione system, P-glycoprotein, PCNA and topoisomerase II expression. P-glycoprotein expression detected by an immunocytochemical technique using MRK 16 antibody was present at the same level in CLL S and CLL R. The percentage of cells positive for P-gp was below 5% in all samples tested. Topoisomerase IIalpha level was quantified by Western blot analysis. None of the 18 CLL samples had detectable topoisomerase IIalpha protein. In addition, 12 CLL were tested for PCNA staining and no samples had more than 1% of positive cells at immunocytochemical detection indicating that CLL cells were not engaged in the cell cycle. Some differences were found between CLL S and CLL R in the glutathione system. Glutathione concentration (GSH) and GST activity was the same in CLL S and CLL R. The glutathione-S-transferase (GST) isoenzyme profile was different in the two CLL groups. The mean GST-pi and GST-alpha quantitation were twice as high as in CLL R compared to CLL S, but this difference did not reach statistical significance because of large variations between CLL samples. A significant correlation was observed between GST-pi expression and GST activity using CDNB as the substrate. GST-mu was detected in only one of seven CLL before therapy and in six of 11 resistant to chemotherapy. No correlation was found between P-glycoprotein expression, GST activity and the different GST isoenzymes studied. These results suggest that the glutathione system could play a role in the resistance of anticancer agents in chronic lymphocytic leukemia. The role of the other drug resistance mechanisms (P-glycoprotein and topoisomerase IIalpha) seems to be of limited importance.
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PMID:Drug resistance mechanisms in chronic lymphocytic leukemia. 894 35

Several antineoplastic agents used in the treatment of hematologic malignancies exert their cytotoxic effects by inhibiting the activity of nuclear DNA topoisomerase (topo) I or II. Mechanisms of drug resistance to topoisomerase inhibitors have been defined at the molecular level from in vitro studies using model cell lines, and include quantitative and qualitative changes in topo I and II. The possible roles of these mechanisms in clinical drug resistance and clinical outcomes for patients with hematologic malignancies are now under investigation. Available data indicate that the blast content of topo II does not correlate with clinical outcome in acute myeloid leukemia (AML), and this may also be true in acute lymphocytic leukemia (ALL). Chronic lymphocytic leukemia (CLL) cells are resistant to topo II inhibitors because they express low levels of topo II. Further studies using sequential biopsy samples and assays of topoisomerase activity should establish the role that changes in topo I and II activity play in the development of drug resistance in hematologic malignancies.
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PMID:Drug resistance to DNA topoisomerase I and II inhibitors in human leukemia, lymphoma, and multiple myeloma. 940 61

B-chronic lymphocytic leukaemia (B-CLL) is characterized by the accumulation of long-lived CD5+ B lymphocytes. The effect of mitoxantrone, a topoisomerase II inhibitor, on B-CLL cells was studied. Treatment of B-CLL cells for 48 h with mitoxantrone (0.5 microg/ml) induced a decrease in cell viability as determined by MTT assay. The IC50 calculated for the cells of three patients was 0.7 microg/ml for two of them and 1.4 microg/ml for the third. In all three patients the maximum effect was observed with 2 microg/ml. An additive cytotoxic effect was observed when mitoxantrone (0.5 microg/ml) was combined with fludarabine (5 microg/ml). Mitoxantrone induced DNA fragmentation and the proteolytic cleavage of poly(ADP-ribose) polymerase (PARP), a marker of the activation of caspases, in all the patients studied, demonstrating that the cytotoxic effect of mitoxantrone was due to induction of apoptosis. These results suggest that mitoxantrone, and possibly other topoisomerase II inhibitors, may be used in the chemotherapy of B-CLL, and that combination of mitoxantrone with fludarabine or other drugs could improve the effectiveness of the treatment.
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PMID:Mitoxantrone, a topoisomerase II inhibitor, induces apoptosis of B-chronic lymphocytic leukaemia cells. 945 Aug 3

Elevated expression of the membrane transporter p-glycoprotein (pgp) and impaired expression of the nuclear enzyme topoisomerase II (topo II) are well-known mechanisms for in vitro acquired drug resistance. The clinical relevance of topo II remains unclear, whereas a relationship between pgp levels and treatment results has been shown in acute myelogenous leukaemia (AML). We have investigated the relationships between the levels of topo II and pgp, and in vitro sensitivity to etoposide in mononuclear blood cells from 24 patients with AML, 16 with chronic lymphocytic leukaemia (CLL) and five healthy blood donors. Following incubation with etoposide, AML cells showed more DNA damage, determined by a DNA unwinding technique, than CLL cells (P = 0.001), whereas there was no difference in cellular etoposide accumulation. Pgp and topo IIbeta levels, determined by Western blot, showed a pronounced variation between patients, but no correlation with induced DNA damage, whereas topo IIalpha protein was undetectable. In the AML group, topo IIbeta expression correlated with pgp expression (rho = 0.7, P = 0.001, n = 24). The topo IIbeta expression was 147.4(+/-74.6)% in the pgp+ AML cells (n = 10), compared to 33.4(+/-27.8)% in pgp- AML cells (n = 14) (P = 0.0001). Our results show a previously unknown coexpression of topo IIbeta and pgp in AML, thereby suggesting that topo IIbeta is a potentially interesting resistance factor in AML.
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PMID:Etoposide-induced DNA strand breaks in relation to p-glycoprotein and topoisomerase II protein expression in leukaemic cells from patients with AML and CLL. 1023 13

Previous studies have demonstrated alkylating (melphalan) resistance in the B-CLL derived WSU-CLL cell line as compared to WIL2 B lymphocytic cells. Nuclear extracts from WSU-CLL cells demonstrate a highly significant increase in DNA topoisomerase II activity as compared to WIL2 cells. Western blot analysis showed the level of topoisomerase II proteins expressed in WSU-CLL cells to be increased as compared to WIL2 cells. WSU-CLL cells were 5.24-fold more sensitive than WIL2 cells to the cytotoxic effect of the topoisomerase II inhibitor doxorubicin. No difference in topoisomerase I activity or of the level of topoisomerase I protein expression was observed comparing the two cell lines. The sensitivity to the cytotoxic effects of topoisomerase I inhibitor, camptothecin, did not differ in WSU-CLL and WIL2 cell lines. Pre-incubation with doxorubicin significantly increased melphalan induced interstrand-DNA-crosslink formation and cytotoxicity in WSU-CLL cells as compared to WIL2 cells. The affinity of topoisomerase II for WSU-CLL UV-irradiated-crosslinked DNA was increased 2.84-fold as compared to that of WSU-CLL native DNA. The affinity of topoisomerase II for both UV-irradiated (crosslinked) and for native DNA was significantly decreased after doxorubicin-pretreatment. Measurement of DNA polymerase beta and DNA polymerase beta revealed significant elevations in DNA polymerase beta (58.82 +/- 3.67 units/mg protein in WSU-CLL cells, as compared to 27.82 +/- 4.39 units/mg protein in WIL 2 cells; p < 0.01) but not DNA polymerase beta (0.82 +/- 0.11 units/mg protein in WSU-CLL cells, compared to 0.74 +/- 0.09 units/mg protein in WIL2, p > 0.05). However, exposure to aphidicolin (an inhibitor of DNA polymerase a) failed to increase melphalan induced cytotoxicity suggesting that although DNA polymerase a activity was increased in WSU-CLL cells the mechanisms of resistance does not involve this specific DNA repair pathway. Elevated topoisomerase II activity and the increased affinity of topoisomerase II for crosslinked DNA in melphalan resistant cells appears to be the major factor responsible for alkylator resistance by changing DNA topology and thereby facilitating DNA repair.
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PMID:Alkylator resistance in human B lymphoid cell lines: (2). Increased levels of topoisomerase II expression and function in a melphalan-resistant B-CLL cell line. 1095 28

Chronic lymphocytic leukemia (CLL) is rarely associated with secondary acute myelogenous leukemia (AML) usually due to chemotherapy or radiotherapy. No cases of concomitant CLL and acute promyelocytic leukemia (APL) have been found in the literature. Nevertheless, up to 12% of therapy-related AML cases are classified as APL. Of these latter, most are related to topoisomerase treatment, with a few acute cases occurring after radiotherapy. We report here a patient with an untreated CLL who developed APL 2 years after radiotherapy for prostate carcinoma.
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PMID:Acute promyelocytic leukemia developing after radiotherapy for prostate cancer in a patient with chronic lymphocytic leukemia. 1175 54


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