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PubMed1994

Association between the p170 form of human topoisomerase II and progeny viral DNA in cells infected with herpes simplex virus type 1.

Endogenous host topoisomerase II acts upon herpes simplex virus type 1 (HSV-1) DNA in infected cells (S.N. Ebert, S.S. Shtrom, and M.T. Muller, J. Virol. 56:4059-4066, 1990), and cleavage is directed exclusively at progeny viral DNA while parental DNA is resistant. To evaluate the possibility that HSV-1 induces topoisomerase II activity which could account for the preferential cleavage of progeny viral DNA, we assessed topoisomerase II cleavage activity on cellular and viral DNA substrates before and after the initiation of viral DNA replication. We show that cleavage of a host gene in mock-infected cells was similar to that observed in HSV-1-infected cells, regardless of whether viral DNA replication had occurred. In addition, quantitative measurements revealed comparable amounts of topoisomerase II activity in infected and mock-infected cells; thus, HSV-1 neither induces nor encodes its own type II topoisomerase and cleavages in vivo are due to a preexisting host topoisomerase. Human cells contain two isozymes of topoisomerase II (p170 and p180), encoded by separate genes. Through the use of isozyme-specific antibodies, we demonstrate that only p170 was found to be cross-linked to HSV-1 DNA even though both forms were present at nearly constant levels in HSV-1-infected cells. Immunofluorescence revealed that by 6 h postinfection, p170 becomes redistributed and localized to sites of active viral DNA synthesis. The data suggest that p170 gains preferential access to replicated viral DNA molecules, which explains why topoisomerase II activity is concentrated on progeny DNA.

Amino Acid Sequence↗

PubMed1991

Chromatin structure, not DNA sequence specificity, is the primary determinant of topoisomerase II sites of action in vivo.

In the studies reported here we have used topoisomerase II as a model system for analyzing the factors that determine the sites of action for DNA-binding proteins in vivo. To localize topoisomerase II sites in vivo we used an inhibitor of the purified enzyme, the antitumor drug VM-26. This drug stabilizes an intermediate in the catalytic cycle, the cleavable complex, and substantially stimulates DNA cleavage by topoisomerase II. We show that lysis of VM-26 treated tissue culture cells with sodium dodecyl sulfate induces highly specific double-strand breaks in genomic DNA, and we present evidence indicating that these double-strand breaks are generated by topoisomerase II. Using indirect end labeling to map the cleavage products, we have examined the in vivo sites of action of topoisomerase II in the 87A7 heat shock locus, the histone repeat, and a tRNA gene cluster at 90BC. Our analysis reveals that chromatin structure, not sequence specificity, is the primary determinant in topoisomerase II site selection in vivo. We suggest that chromatin organization may provide a general mechanism for generating specificity in a wide range of DNA-protein interactions in vivo.

Animals↗

PubMed1997

Clusters of S1 nuclease-hypersensitive sites induced in vivo by DNA damage.

DNA end-labeling procedures were used to analyze both the frequency and distribution of DNA strand breaks in mammalian cells exposed or not to different types of DNA-damaging agents. The 3' ends were labeled by T4 DNA polymerase-catalyzed nucleotide exchange carried out in the absence or presence of Escherichia coli endonuclease IV to cleave abasic sites and remove 3' blocking groups. Using this sensitive assay, we show that DNA isolated from human cells or mouse tissues contains variable basal levels of DNA strand interruptions which are associated with normal bioprocesses, including DNA replication and repair. On the other hand, distinct dose-dependent patterns of DNA damage were assessed quantitatively in cultured human cells exposed briefly to menadione, methylmethane sulfonate, topoisomerase II inhibitors, or gamma rays. In vivo induction of single-strand breaks and abasic sites by methylmethane sulfonate was also measured in several mouse tissues. The genomic distribution of these lesions was investigated by DNA cleavage with the single-strand-specific S1 nuclease. Strikingly similar cleavage patterns were obtained with all DNA-damaging agents tested, indicating that the majority of S1-hypersensitive sites detected were not randomly distributed over the genome but apparently were clustered in damage-sensitive regions. The parallel disappearance of 3' ends and loss of S1-hypersensitive sites during post-gamma-irradiation repair periods indicates that these sites were rapidly repaired single-strand breaks or gaps (2- to 3-min half-life). Comparison of S1 cleavage patterns obtained with gamma-irradiated DNA and gamma-irradiated cells shows that chromatin structure was the primary determinant of the distribution of the DNA damage detected.

Animals↗

PubMed1987

Repair of UV-induced lesions in Xenopus laevis oocytes.

We characterized a DNA repair system in frog oocytes by comicroinjection of UV-irradiated pBR322 DNA and radiolabeled nucleotides. Repair synthesis was monitored by incorporation of label into recovered pBR322 DNA and by a novel method in which the removal of UV photoproducts was determined from the shift of DNA topoisomers that occurs during gel electrophoresis upon repair of these lesions. We investigated the effects of several drugs in the oocyte system and found that although novobiocin, an inhibitor of topoisomerase II, was an effective inhibitor of repair, VM-26, another inhibitor of topoisomerase II, was not. In addition, the topoisomerase I inhibitor camptothecin had no effect on repair in this system. Finally, circular DNA (either supercoiled or nicked circular) was repaired at least 50 times more rapidly than linear DNA.

Animals↗

PubMed1988

Swiveling and decatenation of replicating simian virus 40 genomes in vivo.

We have found that type II topoisomerase inhibitors have two effects on replicating simian virus 40 genomes in vivo: production of catenated dimers and slowed replication of the last 5% of the genome. This suggests that type II topoisomerase simultaneously decatenates and facilitates replication fork movement at this stage of DNA replication. On the basis of this observation, a detailed model is proposed for the roles of topoisomerases I and II in simian virus 40 DNA replication.

Animals↗

PubMed2004

Overexpression of a dominant-negative mutant Ubc9 is associated with increased sensitivity to anticancer drugs.

Ubc9 is an E2-conjugating enzyme required for sumoylation and has been implicated in regulating several critical cellular pathways. We have shown previously that Ubc9 is important for sumoylation and nucleolar delocalization of topoisomerase (topo) I in response to topo I inhibitors such as topotecan. However, the role for Ubc9 in tumor drug responsiveness is not clear. In this study, we found that although MCF7 cells expressing a Ubc9 dominant-negative mutant (Ubc9-DN) display decreased activity of topo I, these cells are more sensitive to the topo I inhibitor topotecan and other anticancer agents such as VM-26 and cisplatin. In addition, we found that alteration of Ubc9 expression correlates with drug responsiveness in tumor cell lines. To understand possible mechanisms of Ubc9-associated drug responsiveness, we examined several proteins that have been shown to interact with Ubc9 and that may be involved in drug responsiveness. One such protein is Daxx, which is a Fas-associated protein that plays a role in Fas-mediated apoptosis by participating in a caspase-independent pathway through activation of apoptosis signal-regulating kinase 1 and c-Jun NH(2)-terminal kinase. We found that cells expressing Ubc9-DN accumulate more cytoplasmic Daxx than the control cells. Because cytoplasmic Daxx is believed to participate in cellular apoptosis, we suggest that the interaction of Ubc9 with Daxx and subsequent alteration in the subcellular localization of Daxx may contribute to the increased sensitivity to anticancer drugs in the cells expressing Ubc9-DN. Finally, we found that overexpression of Daxx sensitizes cells to anticancer drugs possibly in part through alterations of the ratio of cytoplasmic and nuclear Daxx. Together, our results suggest a role for Ubc9 in tumor drug responsiveness.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Evasion of a single-step, chemotherapy-induced senescence in breast cancer cells: implications for treatment response.

PURPOSE: The purpose of this study is to define the mechanistic basis for recovery of proliferative capacity in breast tumor cells after chemotherapy. Here, we test the hypothesis that evasion of senescence confers resistance to chemotherapeutic drugs and ionizing radiation. EXPERIMENTAL DESIGN: MCF-7 cells were treated with a single, clinically relevant dose (0.75-1.0 micromol/L) of Adriamycin. Two weeks following induction of senescence, clonal outgrowths were expanded and characterized in terms of senescence-associated beta-galactosidase activity, gene expression profiles (Affymetrix U95 probe sets, Affymetrix, Santa Clara, CA) with confirmatory Western analyses, and telomerase activity following a second drug treatment. Levels of intracellular Adriamycin, as well as cross-resistance to other therapeutic agents, were also determined to define the resistance phenotype. RESULTS: A senescence-resistant (SR) clone (clone 2) was identified that was largely refractory to both Adriamycin-induced and gamma-irradiation-induced senescence. Clone 2 continued to proliferate and maintain high levels of telomerase activity following a second drug treatment, when treated parental cells expressed very low levels of telomerase and many positive cell cycle regulators. SR clone 2 also expressed substantially more cdc-2 than parental cells and undetectable levels of MDR1, showed an intact p53 checkpoint and only a modestly lower level of intracellular drug accumulation, while exhibiting cross-resistance to other topoisomerase inhibitors. CONCLUSIONS: SR clone 2 is intrinsically resistant to DNA damage-induced senescence perhaps through an ability to prevent down-regulation of cdc-2. Telomerase is a marker of proliferative recovery for breast cancer cells after chemotherapy exposure. Evasion or escape from a single-step, drug-induced senescence may represent a unique and previously unrecognized drug-resistance phenotype.

Antibiotics, Antineoplastic↗

PubMed2005

Synergistic interaction between histone deacetylase and topoisomerase II inhibitors is mediated through topoisomerase IIbeta.

BACKGROUND: DNA topoisomerase II inhibitors and poisons are among the most efficacious drugs for the treatment of cancer. Sensitivity of cancer cells to the cytotoxic effects of topoisomerase II targeting agents is thought to depend on the expression of the topoisomerase IIalpha isoform, and drug resistance is often associated with loss or mutation of topoisomerase IIalpha. Histone deacetylase inhibitors (HDACi) are a novel class of compounds that potentiate the antitumor effects of topoisomerase II-targeting agents. METHODS: The interaction between HDACi and topoisomerase II-targeting agents in cancer cells was evaluated as a function of topoisomerase IIalpha and topoisomerase IIbeta expression. Topoisomerase II isoforms were selectively depleted using small interfering RNA and antisense. Drug-induced formation of cleavable complexes involving topoisomerase IIalpha and topoisomerase IIbeta was evaluated by trapped-in-agarose DNA immunostaining and band depletion assays in the presence and absence of HDACi. RESULTS: Preexposure to HDACi increased the cytotoxicity of topoisomerase II poisons. This was associated with a down-regulation of topoisomerase IIalpha expression but had no effects on topoisomerase IIbeta. In the setting of HDACi-induced chromatin decondensation and topoisomerase IIalpha depletion, topoisomerase II poison cytotoxicity was mediated through topoisomerase IIbeta cleavable complex formation. The HDACi-induced sensitization was also observed in cells with target-specific resistance to topoisomerase II poisons. CONCLUSIONS: The recruitment of topoisomerase IIbeta as a target may overcome primary or emergent drug resistance to topoisomerase II-targeting agents and hence may broaden the applicability of this important class of anticancer agents.

Antineoplastic Agents↗

PubMed1978

[Induction chemotherapy of non-Hodgkin malignant lymphomas. Results of a controlled trial comparing two quadruple associations (author's transl)].

Two types of chemotherapy have been compared in a randomized trial to treat non-Hodgkin malignant lymphomas. 66 patients were included in this study, but only 40 were evaluable after a histologic review of all cases. Treatment were an association of cyclophosphamide, vincristine, prednisone and doxorubicine or VM 26. Patients received only one induction chemotherapy course during 15--20 days. Results were evaluated immediately at the end of the course. Side-effects were mild. Efficacy was about the same with the two protocols: 35 patients out of 40 experienced a remission of more than 50% (among them 8 experienced a complete remission). These results are better than previous one obtained with cyclophosphamide, vincristine and prednisone only. It is concluded that this type of treatment is well tolerated, quickly efficient and useful before treating patients with radiotherapy or long-term chemotherapy.

Antineoplastic Agents↗

PubMed1975

Results obtained with combination therapy of VM-26, natulan and prednisolone in generalized Hodgkin's disease.

By evaluating the results obtained in 50 patients the authors stated that VM-26 given in combination with Natulan and Prednisolone is a drug of value in the therapy of generalized Hodgkin's disease. It cause milder side effects than drugs previously used in combination therapy. Complete or partial remissions were obtained in 84% of patients treated. 75% of the therapy-resistant cases proved to be Hodgkin's sarcoma by the postmortem examination. Remission lasted longer in stage III than in stage IV and the previously untreated patients responded better than the treated one. Definite correlation could not be revealed between histologic type and duration of remission.

Adolescent↗

PubMed1978

Effects of the epipodophyllotoxin derivative VM 26 in mitosis and in interphase.

The epipodophyllotoxin derivative VM 26 inhibits entry of mouse mastocytoma cells into mitosis in cell cultures at drug concentrations of 0.01--1 microgram/ml, the cells being arrested in G2 phase of the cell cycle. At higher concentrations, the compound exhibits spindle poison activity which manifests itself in a shortlasting rise in the number of cells arrested in metaphase of mitosis. These cells then disintegrate after a short period of time.

Animals↗

PubMed1987

Combination chemotherapy of hepatocellular cancer. Comparison of adriamycin + VM 26 + 5-fluorouracil with mAMSA + VM 26 + 5-fluorouracil.

Forty-seven patients with hepatocellular cancer were treated in a randomised trial comparing adriamycin + VM 26 + 5-Fluorouracil (5-FU) to mAMSA + VM 26 + 5-FU. Thirteen patients had a partial response to treatment (28%) and another 6 (13%) showed disease stabilisation. There were no significant differences in the response rates between the two treatment regimens. Patients who responded to treatment showed significant prolongation of survival (48 weeks) when compared to non-responders (5 weeks).

Adult↗

PubMed1976

Single-drug chemotherapy of bladder cancer with adriamycin, VM-26 or bleomycin. A phase II multicentric, co-operative study.

Single-drug chemotherapy was employed in a multicentric co-operative trial. Adriamycin was given to 18 patients, VM-26 to 30 and Bleomycin to 33. Almost all patients were suffering from a T3 or T4 bladder cancer with known metastases in almost 40% of cases. The vast majority of patients had already received previous treatment either chemotherapy, surgery of irradiation. Complete regression was obtained in 5% of cases; partial objective regression in 11.1% of patients treated with Adriamycin, 26.6% with VM-26 and 33.3% with Bleomycin. The results were uniformly better when high dosages of drug were employed. No clear-cut superiority of one drug over the others can be demonstrated.

Bleomycin↗

PubMed1976

EORTC randomized trial for the adjuvant therapy of T1 bladder carcinoma.

A randomized clinical trial was designed by the European Organization for Research on Treatment of Cancer (EORTC) to compare the disease-free interval, the degree of malignancy of recurrence and the 5-year survival rate in stage I papillary carcinoma of the bladder after TUR only, and after TUR followed either by local thiotepa or by local VM 26 chemotherapy.

Carcinoma, Papillary↗

PubMed1982

Prophylactic chemotherapy of superficial transitional cell bladder carcinoma: an EORTC randomized trial comparing thiotepa, an epipodophyllotoxin (VM26) and TUR alone.

The Urological Group of the European Organization for Research on Treatment of Cancer (EORTC) has performed a randomized clinical trial designed to compare the disease-free interval, the recurrence rate and the number of patients with increase in tumor stage after transurethral resection (TUR) only or TUR followed by prophylactic bladder instillation of thiotepa or VM26 (an epipodophyllotoxin derivative). Drug instillation was initiated 1 month after TUR and subsequently administered weekly for 4 weeks and then monthly for 1 year. 370 patients from 20 participating institutions in six different countries were admitted to this protocol. 308 eligible patients with follow-up were analyzed. There was no difference among the groups regarding the time of first recurrence (disease-free interval) but thiotepa significantly reduced the recurrence rate as compared to the control group or VM26. When adjusting for primary or recurrent patients stratification, the results remained the same.

Carcinoma, Transitional Cell↗

PubMedDate not supplied

Preradiation chemotherapy with VM-26 and CCNU in patients with glioblastoma multiforme.

AIMS AND BACKGROUND: The objective of the study was to evaluate the efficacy of combined chemoradiation in patients with newly diagnosed glioblastoma multiforme. The main end points were time to progression and overall survival. METHODS: Thirty-one patients with glioblastoma multiforme underwent surgery whenever possible and then received intravenous VM26 (120 mg/m2) and oral CCNU (120 mg/m2) for three cycles followed by radiotherapy (60 Gy). RESULTS: Surgery consisted of a complete resection in 39% of patients, partial resection in 35% and a biopsy in 26%. Sixteen patients had clinical or radiological evidence of progression during or after chemotherapy. Hematologic toxicity was mild. Forty-five percent of patients received the scheduled dose of radiation. The outcome was disappointing, with a median time to progression of 18 weeks and median survival of 37.17 weeks. CONCLUSIONS: The survival of patients with glioblastoma multiforme remains disappointing. Multimodal therapy does not seem to modify the evolution of the tumor. Stratification according to prognostic factors might detect a potential benefit of other therapeutic approaches.

Administration, Oral↗

PubMed1981

VM 26 in advanced mycosis fungoides.

Five consecutive patients with progressive extracutaneous stage IV mycosis fungoides (MF) were treated with VM 25, 100 mg/m2 i.v., for at least 3 cycles. All patients had been extensively pretreated and in particular with vinca alkaloids. Two partial responses of 5 and 9+ months duration and 1 minimal response of 5 months duration were obtained. Transient myelosuppression was encountered in all patients. These preliminary results should encourage further exploration of VM 26, even in less advanced MF.

Adult↗

PubMed1981

Combination chemotherapy for metastatic brain tumors.

Forty-four patients with central nervous system metastases were treated with combination chemotherapy (adriamycin, VM 26 and CCNU). The best results were obtained in breast adenocarcinoma and small cell lung carcinoma with multiple, small cerebral metastases and without concomitant visceral involvement at other sites. The potential effectiveness of this regimen to prevent cerebral metastases is discussed.

Adenocarcinoma↗