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PubMed2005

[Standards and new developments in the chemotherapy of glioblastomas].

For 25 years involved-field radiotherapy has remained the mainstay of postoperative treatment for glioblastoma. In contrast, the role of adjuvant chemotherapy in addition to radiotherapy has remained controversial. A recent randomized multinational phase III trial (EORTC 26 981/22 981/NCIC CE.3) assessing concomitant and adjuvant chemotherapy with the alkylating agent, temozolomide, in addition to radiotherapy in newly diagnosed glioblastoma defines an increase in median survival from 12.1 months with radiotherapy alone to 14.6 months with radiochemotherapy and an increase in the 2-year survival rate from 10 to 26 %. Subgroup analysis revealed that the gain in survival in the experimental arm was largely achieved in patients with glioblastomas which exhibited a methylation of the promoter region of the O (6)-methylguanine DNA methyltransferase (MGMT) gene and thus did not express MGMT. MGMT is a DNA repair enzyme which repairs DNA lesions induced by chemotherapy with alkylating agents. The cellular MGMT stores are consumed during DNA repair, suggesting that temozolomide itself may deplete MGMT and thus overcome its own most important pathway of resistance. EORTC 26 981/22 981/NCIC CE.3 thus defines a milestone in the treatment of glioblastoma and will provide a platform for further efforts at improving the outcome for patients suffering from this still invariably fatal neoplasm.

Antineoplastic Agents, Alkylating↗
PubMedDate not supplied

[Hypersensitivity to VM-26].

Life-threatening anaphylactic reactions to VM-26 are rare. In this report two patients with anaphylactic reactions after the first VM-26 applications in the German neuroblastoma therapy protocol GPO-NB-82 are described. After combination of VM-26 with dexamethasone, repetition of these reactions did not occur any more.

Adrenal Cortex Neoplasms↗
PubMed1990

[Chemotherapy in malignant gliomas].

Considering the survival time of patients with malignant gliomas indication for chemotherapy in spite of side effects is recommended. One third of them are living 2 years, some even longer. Before starting such a treatment a critical evaluation is mandatory, a prolongation of dying must be avoided. In addition personal human care to the patient and his family has a great importance.

Antineoplastic Agents↗
PubMed2003

The topoisomerase IIbeta circular clamp arrests transcription and signals a 26S proteasome pathway.

It has been proposed that the topoisomerase II (TOP2)beta-DNA covalent complex arrests transcription and triggers 26S proteasome-mediated degradation of TOP2beta. It is unclear whether the initial trigger for proteasomal degradation is due to DNA damage or transcriptional arrest. In the current study we show that the TOP2 catalytic inhibitor 4,4-(2,3-butanediyl)-bis(2,6-piperazinedione) (ICRF-193), which traps TOP2 into a circular clamp rather than the TOP2-DNA covalent complex, can also arrest transcription. Arrest of transcription, which is TOP2beta-dependent, is accompanied by proteasomal degradation of TOP2beta. Different from TOP2 poisons and other DNA-damaging agents, ICRF-193 did not induce proteasomal degradation of the large subunit of RNA polymerase II. These results suggest that proteasomal degradation of TOP2beta induced by the TOP2-DNA covalent complex or the TOP2 circular clamp is due to transcriptional arrest but not DNA damage. By contrast, degradation of the large subunit of RNA polymerase II is due to a DNA-damage signal.

Animals↗
PubMed1990

Cell cycle synchronization: reversible induction of G2 synchrony in cultured rodent and human diploid fibroblasts.

In accord with a set of prespecified principles of cell synchrony induction, a three-step procedure was developed to arrest cells reversibly in the G2 phase of the cell cycle. Cultures of Chinese hamster ovary (CHO) cells were presynchronized in early S phase by sequential treatment with isoleucine deficiency and hydroxyurea blockades; then they were switched to medium supplemented with either of two agents that inhibit DNA topoisomerase II activity by different mechanisms, Hoechst 33342 at 7.5 micrograms/ml for 12 hr or VM-26 at 0.5 micrograms/ml for 8 hr. Up to 95% of the cells accumulated in G2 phase under those conditions. After switch of Hoechst 33342-treated cells to drug-free medium, the cells divided as a highly synchronized cohort of cells within 3 hr. Up to 85% of the cells in a culture of human diploid dermal fibroblasts (HSF-55 cells) could be accumulated in G2 phase by placing cells presynchronized in early-S phase in medium containing Hoechst 33342 at 0.1 micrograms/ml for 10 hr. Reversal of G2 arrest in the HSF-55 cultures resulted in cells dividing synchronously over 3.5 hr. By varying the concentration of Hoechst 33342 and the duration of the treatment period, it was possible to alter the position within G2 phase at which cells accumulated. This synchronization protocol should greatly facilitate study of G2/M biochemical events in mammalian cells, in particular, those associated with cdc2 gene regulation of the onset of mitosis.

Animals↗
PubMed1991

Precise localization of the alpha-globin gene cluster within one of the 20- to 300-kilobase DNA fragments released by cleavage of chicken chromosomal DNA at topoisomerase II sites in vivo: evidence that the fragments are DNA loops or domains.

We have mapped the position of the alpha-globin gene cluster in the 20- to 300-kilobase fragments of chromosomal DNA isolated from growing chicken HD3 erythroblastoid cells exposed to 4'-demethylepipodophyllotoxinthenylidene beta-D-glucoside. This epipodophyllotoxin traps functioning topoisomerase II molecules, the denaturation of which cleaves DNA and reveals their reaction sites. The DNA fragments, prepared by centrifugation in sucrose gradients, bind selectively to glass-fiber filters and are protected from lambda 5'-exonuclease, properties compatible with the presence of a topoisomerase II subunit bound to their 5' ends. Restriction enzyme cleavage of the fragments and hybridization with cloned alpha-globin-region probes reveal additional distinctive bands not seen in control DNA, allowing the localization of fragment ends near this gene cluster. The terminal regions of fragments from sucrose gradients or from field-inversion electrophoresis gels were also used to probe cloned regions of the gene cluster. Both approaches show that this cluster of three genes, which is not expressed in these cells, is located at a specific position in a approximately 20-kilobase DNA fragment. The upstream end of this fragment lies in a region that contains a site of DNA attachment to the nuclear matrix mapped by both in vivo and in vitro methods, and its downstream end is flanked by approximately 80% A + T sequences characteristic of matrix-attachment regions. These observations suggest that the DNA fragments are formed because topoisomerase II molecules can specifically and readily integrate into DNA at matrix-attachment regions and that the fragments represent entire DNA loops or domains.

Animals↗
PubMed1992

2-Aminopurine overrides multiple cell cycle checkpoints in BHK cells.

BHK cells blocked at any of several points in the cell cycle override their drug-induced arrest and proceed in the cycle when exposed concurrently to the protein kinase inhibitor 2-aminopurine (2-AP). For cells arrested at various points in interphase, 2-AP-induced cell cycle progression is made evident by arrival of the drug-treated cell population in mitosis. Cells that have escaped from mimosine G1 arrest, from hydroxyurea or aphidicolin S-phase arrest, or from VM-26-induced G2 arrest subsequently have all the hallmarks of mitosis--such as a mitotic microtubule array, nuclear envelope breakdown, and chromatin condensation. In a synchronous population, the time course of arrival in mitosis and its duration in 2-AP-treated cells that have escaped drug-induced cell cycle blocks is indistinguishable from control cells. Cells arrested in mitosis by nocodazole or taxol quickly escape mitotic arrest and enter interphase when exposed to 2-AP. 2-AP by itself does not influence the timing of cell cycle progression. We conclude that 2-AP acts to override checkpoints in every phase of the cell cycle, perhaps by inhibiting a protein kinase responsible for control of multiple cell cycle checkpoints.

2-Aminopurine↗
PubMed1995

Different topoisomerase II antitumor drugs direct similar specific long-range fragmentation of an amplified c-MYC gene locus in living cells and in high-salt-extracted nuclei.

We have analyzed the long-range distribution of topoisomerase II-mediated cleavages induced in an amplified human c-MYC gene locus in the presence of several antitumor agents. The long-range cleavage patterns were found to be nonrandom and similar for all antitumor drugs tested. Cleavages occurred within several kilobase-long areas (approximately 5 kb) highly accessible to topoisomerase II and separated by extended regions (approximately 70-100 kb) of less accessibility, possibly reflecting the mode of DNA organization into loops along the chromosome. Within the cleavage areas, the patterns of cleavage sites showed a certain dependence on the type of drug used for entrapment of topoisomerase II-DNA complexes. Importantly, distribution of cleavage areas in native chromatin and histone-depleted nuclei was very similar, if not identical, suggesting that the primary target of antitumor agents in vivo is topoisomerase II associated with the high-salt-insoluble nuclear matrix. These data show that matrix-attached DNA is preferentially damaged by topoisomerase II-targeting agents, which may be an important cellular event contributing to drug-induced cell death.

Amsacrine↗
PubMed2001

Atp-bound topoisomerase ii as a target for antitumor drugs.

Topoisomerase II (TOP2) poisons interfere with the breakage/reunion reaction of TOP2 resulting in DNA cleavage. In the current studies, we show that two different classes (ATP-sensitive and -insensitive) of TOP2 poisons can be identified based on their differential sensitivity to the ATP-bound conformation of TOP2. First, in the presence of 1 mm ATP or the nonhydrolyzable analog adenosine 5'-(beta,gamma-imino)triphosphate, TOP2-mediated DNA cleavage induced by ATP-sensitive TOP2 poisons (e.g. doxorubicin, etoposide, mitoxantrone, and 4'-(9-acridinylamino)methanesulfon-m-anisidide) was 30-100-fold stimulated, whereas DNA cleavage induced by ATP-insensitive TOP2 poisons (e.g. amonafide, batracylin, and menadione) was only slightly (less than 3-fold) affected. In addition, ADP was shown to strongly antagonize TOP2-mediated DNA cleavage induced by ATP-sensitive but not ATP-insensitive TOP2 poisons. Second, C427A mutant human TOP2alpha, which exhibits reduced ATPase activity, was shown to exhibit cross-resistance to all ATP-sensitive but not ATP-insensitive TOP2 poisons. Third, using ciprofloxacin competition assay, TOP2-mediated DNA cleavage induced by ATP-sensitive but not ATP-insensitive poisons was shown to be antagonized by ciprofloxacin. These results suggest that ATP-bound TOP2 may be the specific target of ATP-sensitive TOP2 poisons. Using Lac repressor-operator complexes as roadblocks, we show that ATP-bound TOP2 acts as a circular clamp capable of entering DNA ends and sliding on unobstructed duplex DNA.

Adenosine Triphosphate↗
PubMed2001

26 S proteasome-mediated degradation of topoisomerase II cleavable complexes.

DNA topoisomerase II (TOP2) cleavable complexes represent an unusual type of DNA damage characterized by reversible TOP2-DNA cross-links and DNA double strand breaks. Many antitumor drugs and physiological stresses are known to induce TOP2 cleavable complexes leading to apoptotic cell death and genomic instability. However, the molecular mechanism(s) for repair of TOP2 cleavable complexes remains unclear. In the current studies, we show that TOP2 cleavable complexes induced by the prototypic TOP2 poison VM-26 are proteolytically degraded by the ubiquitin/26 S proteasome pathway. Surprisingly the TOP2beta isozyme is preferentially degraded over TOP2alpha isozyme. In addition, transcription inhibitors such as 5,6-dichlorobenzimidazole riboside and camptothecin can substantially block VM-26-induced TOP2beta degradation. These results are consistent with a model in which the repair of TOP2beta cleavable complexes may involve transcription-dependent proteolysis of TOP2beta to reveal the protein-concealed double strand breaks.

Animals↗
PubMed2002

Assessment of drug activity and proliferation ex vivo for prediction of outcome in aggressive non-Hodgkin's lymphomas.

The activity of cytotoxic drugs and tumour cell proliferation rate were assessed ex vivo using the fluorometric microculture cytotoxicity assay (FMCA) and stainings for Ki67 and mitosis in 40 patients with aggressive non-Hodgkin's lymphomas (NHL). The findings were correlated to clinical response and survival. Twenty-three patients had a complete remission and 10 a partial remission. A drug sensitivity index based on the cell survival for three major drugs in NHL treatment was derived empirically and proliferation was expressed as low-, intermediate- or high. In 5 out of 8 drugs tested, cell survival ex vivo was higher in clinical non-responders than that in responders. Using the median drug sensitivity index as a cut-off, the sensitivity and specificity for tumour response were 58% and 100%, respectively, and was similar for the proliferation index. Both indices combined increased the sensitivity to 73% at retained specificity. Intermediate/high proliferation was significantly associated with impaired survival, whereas the drug sensitivity index was not predictive of survival. Thus, ex vivo assessments of drug sensitivity and proliferation seem to provide prognostic information in aggressive NHL.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Indications for an active process underlying spontaneous and radiation-induced micronucleation in L929 cells.

PURPOSE: To investigate the mechanism of micronucleus formation in irradiated L929 cells. MATERIALS AND METHODS: Radiation-induced micronuclei (MN) of L929 cells isolated at 48 and 72 h after irradiation were processed for detection of DNA-laddering and higher-order chromatin fragments using conventional gel electrophoresis and pulse-field gel electrophoresis. Quantification of double-strand breaks in micronuclei and nuclei was performed with the TdT assay and quantified using image analysis. The number of binucleated cells containing micronuclei (cytochalasin B method) was counted after application of three unspecific endonuclease inhibitors (aurin, ATA, spermine), a topoisomerase II inhibitor (VM-26), administration of two PKC inhibitors (H-7, Gö6983) and after addition of N-acetylsphingosine (C2-ceramide). PKC activity was determined by measuring the incorporation of [gamma-32P]ATP into a suitable specific substrate. Proliferation was measured by detection of PCNA, RFP-A and BrdU (30-min pulse labelling) using both conventional immunofluorescence and laser scanning microscopy. RESULTS: (1) Higher chromatin fragments accumulated in MN with a size as they occur during early stages of apoptosis; (2) the frequency of MN was influenced by drugs known to play an important role in signalling and execution of apoptosis (endonucleases, topoisomerase II, protein kinases, ceramide); (3) MN are characterized by a reduced transcription ability (PCNA, RFP-A). CONCLUSIONS: A proportion of L929 MN may be formed by an active process comparable with the early stages of apoptosis; it may play a role in the re-organization of the damaged genome.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1992

Advantage of post-radiotherapy chemotherapy with CCNU, procarbazine, and vincristine (mPCV) over chemotherapy with VM-26 and CCNU for malignant gliomas.

Between 1981 and 1987, 133 patients with anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM) were treated with surgery and post-operative radiotherapy. 36 AA and 31 GBM patients were treated with adjuvant chemotherapy consisting of CCNU 100 mg/m2 day 1, procarbazine 60 mg/m2 days 1-14, and vincristine 1.4 mg/m2 (max. 2 mg) days 1 and 8, every 6 weeks which we called a "modified PCV" (mPCV) regimen. 37 AA and 29 GBM patients were treated with adjuvant chemotherapy consisting of VM-26 75 mg/m2 days 1 and 2, and CCNU 60 mg/m2 days 3 and 4, every 6 weeks. Prognostic covariates such as patient's age, Karnofsky performance status score and the extent of surgery were balanced between the two treatment groups. The time to tumor progression and survival time for both regimens show that mPCV produces a two-fold increase in these factors at the 50th and 25th percentile for AA patients, but not for GBM patients, although there are more long-term GBM survivors with mPCV than with the VM-26 + CCNU regimen.

Adult↗
PubMed2003

Taxanes in the treatment of advanced (stage III and IV) non-small cell lung cancer (NSCLC): recent developments.

Taxanes, paclitaxel, and docetaxel have become the cornerstone of both first-line and second-line chemotherapy for advanced non-small cell lung cancer (NSCLC). Recently, several pivotal phase III randomized trials have been published. These studies and phase II trials will be discussed. Additionally, studies utilizing a taxane and radiation therapy for resectable and locally advanced NSCLC will be outlined. The article will end with a discussion on newer strategies being currently explored to improve survival in advanced NSCLC.

Angiogenesis Inhibitors↗
PubMed1990

The topoisomerase II inhibitor VM-26 induces marked changes in histone H1 kinase activity, histones H1 and H3 phosphorylation, and chromosome condensation in G2 phase and mitotic BHK cells.

We have examined the effects of topoisomerase inhibitors on the phosphorylation of histones in chromatin during the G2 and the M phases of the cell cycle. Throughout the G2 phase of BHK cells, addition of the topoisomerase II inhibitor VM-26 prevented histone H1 phosphorylation, accompanied by the inhibition of intracellular histone H1 kinase activity. However, VM-26 had no inhibitory effect on the activity of the kinase in vitro, suggesting an indirect influence on histone H1 kinase activity. Entry into mitosis was also prevented, as monitored by the absence of nuclear lamina depolymerization, chromosome condensation, and histone H3 phosphorylation. In contrast, the topoisomerase I inhibitor, camptothecin, inhibited histone H1 phosphorylation and entry into mitosis only when applied at early G2. In cells that were arrested in mitosis, VM-26 induced dephosphorylation of histones H1 and H3, DNA breaks, and partial chromosome decondensation. These changes in chromatin parameters probably reverse the process of chromosome condensation, unfolding condensed regions to permit the repair of strand breaks in the DNA that were induced by VM-26. The involvement of growth-associated histone H1 kinase in these processes raises the possibility that the cell detects breaks in the DNA through their effects on the state of DNA supercoiling in constrained domains or loops. It would appear that histone H1 kinase and topoisomerase II work coordinately in both chromosome condensation and decondensation, and that this process participates in the VM-26-induced G2 arrest of the cell.

Animals↗
PubMed1993

Mitotic repression of transcription in vitro.

A normal consequence of mitosis in eukaryotes is the repression of transcription. Using Xenopus egg extracts shifted to a mitotic state by the addition of purified cyclin, we have for the first time been able to reproduce a mitotic repression of transcription in vitro. Active RNA polymerase III transcription is observed in interphase extracts, but strongly repressed in extracts converted to mitosis. With the topoisomerase II inhibitor VM-26, we demonstrate that this mitotic repression of RNA polymerase III transcription does not require normal chromatin condensation. Similarly; in vitro mitotic repression of transcription does not require the presence of nucleosome structure or involve a general repressive chromatin-binding protein, as inhibition of chromatin formation with saturating amounts of non-specific DNA has no effect on repression. Instead, the mitotic repression of transcription appears to be due to phosphorylation of a component of the transcription machinery by a mitotic protein kinase, either cdc2 kinase and/or a kinase activated by it. Mitotic repression of RNA polymerase III transcription is observed both in complete mitotic cytosol and when a kinase-enriched mitotic fraction is added to a highly simplified 5S RNA transcription reaction. We present evidence that, upon depletion of cdc2 kinase, a secondary protein kinase activity remains and can mediate this in vitro mitotic repression of transcription.

Animals↗
PubMed1997

Chromosomes with two intact axial cores are induced by G2 checkpoint override: evidence that DNA decatenation is not required to template the chromosome structure.

Here we report that DNA decatenation is not a physical requirement for the formation of mammalian chromosomes containing a two-armed chromosome scaffold. 2-aminopurine override of G2 arrest imposed by VM-26 or ICRF-193, which inhibit topoisomerase II (topo II)-dependent DNA decatenation, results in the activation of p34cdc2 kinase and entry into mitosis. After override of a VM-26-dependent checkpoint, morphologically normal compact chromosomes form with paired axial cores containing topo II and ScII. Despite its capacity to form chromosomes of normal appearance, the chromatin remains covalently complexed with topo II at continuous levels during G2 arrest with VM-26. Override of an ICRF-193 block, which inhibits topo II-dependent decatenation at an earlier step than VM-26, also generates chromosomes with two distinct, but elongated, parallel arms containing topo II and ScII. These data demonstrate that DNA decatenation is required to pass a G2 checkpoint, but not to restructure chromatin for chromosome formation. We propose that the chromosome core structure is templated during interphase, before DNA decatenation, and that condensation of the two-armed chromosome scaffold can therefore occur independently of the formation of two intact and separate DNA helices.

2-Aminopurine↗