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At least 847 records · Page 47Linked to original sources
PubMed1979

Malignant gliomas treated after surgery by combination chemotherapy and delayed radiation therapy. Part II. Tolerance to irradiation after chemotherapy.

34 patients operated on for malignant gliomas were successively treated by combination chemotherapy with VM26 and CCNU and conventional radiation therapy with an average dosage of 5,800 Rads, six months after surgery. The general and haematological tolerance of delayed irradiation after chemotherapy was satisfactory. Twelve patients developed neurological complications during or after irradiation. The complications were early in 10 cases, and delayed in 2. They were probably due to tumour growth in five cases, and secondary to irradiation in seven. In four of the seven cases the preradiation chemotherapy seemed to potentiate the radiation effect on the central nervous system.

Brain↗
PubMed1977

Cerebral pseudocysts following chemotherapy of glioblastomas.

Three cases of pseudocysts following surgery and chemotherapy for glioblastomas are reported. Their clinical picture was similar, consisting of intracranial hypertension without primary modification of focal signs. CT scanning has been able to detect the cystic aspect and to eliminate a true tumour recurrence. Medical treatment (steroids or Mannitol) seems inefficient. Evacuation of the cyst is the only efficient method of treatment.

Adult↗
PubMed1996

Inactivation of topoisomerase I or II may lead to recombination or to aberrant replication termination on both SV40 and yeast 2 micron DNA.

Topoisomerase I is believed to be sufficient for early replication of circular viral genomes such as those of SV40 and of yeast plasmids. Topoisomerase II is required for the decatenation of the daughter genomes and probably also for fork elongation during the later stages of SV40 replication. Using the neutral-neutral two-dimensional gel system, we have followed the progression of replication of both SV40 and the yeast 2 micron plasmid under various conditions of topoisomerase inhibition. During SV40 replication, inhibition of topoisomerase II by VP16, VM26 or hypertonic shock (but not by merbarone), and inhibition of topoisomerase I by camptothecin all led to the accumulation of aberrant DNA structures containing two almost completely replicated genomes. These aberrant structures resembled either recombination intermediates or late Cairns structures in which the site of replication termination had shifted and now mapped to a continuum of sites throughout the genome. Replication of the 2 micron plasmid in a topoisomerase II- but not a topoisomerase I-deficient yeast gave rise to very similar structures. The data suggest that inactivation of topoisomerase I or II either stimulates recombination or, by differentially affecting replication fork progression, leads to aberrant replication termination.

Camptothecin↗
PubMed2004

Bone marrow transplantation for therapy-related acute myeloid leukemia in congenital retinoblastoma associated with 13q deletion syndrome.

Children with constitutional deletion of the long arm of chromosome 13 are at risk for retinoblastoma (RB) due to loss of the RB tumor suppressor gene. The prognosis is poor since the tumors are often bilateral, aggressive, and recurrent and the patients often harbor other congenital abnormalities. One further complication is that of therapy-related malignancies later in life. We report a case of allogeneic stem cell transplantation for therapy-related acute myeloid leukemia in an 8-year-old girl after multimodality treatment for refractory bilateral relapsing RB, with excellent outcome in both the ophthalmic and marrow disease.

Acute Disease↗
PubMed1997

Immunohistochemical expression of P-glycoprotein and glutathione S-transferases in cerebral gliomas and response to chemotherapy.

The expression of the drug resistance-related proteins glutathione S-transferases (GST) and P-glycoprotein (Pgp) was analyzed quantitatively in samples of 53 astrocytic gliomas (eight WHO grade 1, 11 WHO grade 2, 9 WHO grade 3 and 25 glioblastomas, WHO grade 4). Sections of these tumors were immunohistochemically stained with antibodies to Pgp (MDR1-gene product) and to GST subclasses alpha, mu and pi. Pgp expression was not detected in tumor cells of the majority of low-grade astrocytomas (69%) and the percentage of Pgp stained cells generally increased with tumor grade. However, 4 of the 34 malignant gliomas were negative. Many neoplastic cells of most tumors were dominantly stained for GST-pi. The other two subclasses were expressed in a less consistent fashion with no linear correlation to grading. Grade 2 astrocytomas exhibited the highest percentage of cells with GST expression. GST-alpha was absent in 9 tumors, GST-mu in 8 and GST-pi in 4. Four tumors showed no expression of any GST subclass or Pgp in neoplastic cells. Of 13 patients 5 with a more favorable clinical course after radiation and chemotherapy had a lower percentage of neoplastic cells immunostained for Pgp and the three GST subclasses than 8 patients with a worse clinical course. These results suggest a relationship between expression of drug resistance-related proteins in gliomas and response to chemotherapy with ACNU/VM26.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Evidence for a constitutive, verapamil-sensitive, non-P-glycoprotein multidrug resistance phenotype in malignant glioma that is unaltered by radiochemotherapy in vivo.

Human malignant gliomas are commonly resistant to chemotherapy. Here, we examined the role of the multidrug resistance (mdr) mechanism in the chemo-resistance of these tumors, using a twofold approach: (i) by assessing a possible mdr phenotype before and after chronic drug exposure of glioma cells in vitro, and (ii) by assessing the modulation of expression of the mdr-associated P-glycoprotein (Pgp) using radiotherapy and serial cycles of chemotherapy in human glioblastoma patients in vivo. T98G, and to a lesser degree, LN-229 human malignant glioma cells exhibit a constitutive mdr phenotype as determined by the modulation of dye transport and by the augmentation of chemosensitivity by the mdr antagonist, verapamil. Thus, coexposure to verapamil enhances the cytotoxicity of vincristine, doxorubicin and VM26 in T98G cells and that of vincristine in LN-229 cells. Chronic exposure of the cells to low concentrations of vincristine and doxorubicin, but not VM26, topotecan or BCNU, moderately enhances the mdr-like phenotype, as assessed by drug expulsion assays. However, chronic exposure to increasing drug concentrations does not significantly alter the sensitivity to the respective drugs. These data are consistent with a constitutive, but not drug-inducible, mdr-like drug resistance in glioma cells in vitro. Immunocytochemical analysis of human malignant gliomas in vivo reveals that Pgp expression is more abundant in endothelial cells within the gliomas, than in the glioma cells proper. Importantly, Pgp expression is unaltered by radiochemotherapy, assessed by comparative immunocytochemistry of glioma specimens obtained serially before and after radiochemotherapy. We conclude that (i) glioma cells exhibit constitutive mdr-like drug resistance that is not significantly altered by chronic drug exposure in vitro; (ii) endothelial cells may play an important role in Pgp-mediated drug resistance of gliomas in vivo; (iii) radiotherapy and repeated chemotherapy cycles do not modulate Pgp expression in human malignant gliomas in vivo; (iv) there is preliminary evidence for a non-Pgp, verapamil-sensitive drug transport activity in glioma cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Clinical trial of CPT-11 and VM-26/VP-16 for patients with recurrent malignant brain tumors.

CPT-11 is a potent inhibitor of topoisomerase I and has shown antitumor activity in brain xenografts and in clinical trials in recurrent/progressive malignant glioma. VM-26 and VP-16 are topoisomerase II inhibitors and have also shown activity in phase II trials. We performed a phase II trial of intravenous CPT-11 (125 mg/m2) followed 24 h later by VM-26 (125 mg/m2). VP-16 (125 mg/m2) was later substituted for VM-26 due to drug shortage. For patients on anticonvulsants, the starting dose for all drugs was 150 mg/m2. Drugs were given weekly for 3 weeks followed by 1-week rest. Twenty-five patients were entered into the study. Three patients (12%) had improvement in CAT/MRI brain scans (95% confidence interval 3-31%). Fatigue and myelosuppression, mainly leukopenia, were the main toxicities. This combination of the topoisomerase I inhibitor CPT-11 followed by the topoisomerase II inhibitor, VM-26 or VP-16, has shown modest antitumor activity comparable to that reported for each drug singly. Myelosuppression is the main toxicity when topoisomerase I and II inhibitors are combined together.

Adult↗
PubMed1987

Age as the main prognostic factor in adult aggressive non-Hodgkin's lymphoma.

From 1975 to 1983, 73 patients with aggressive non-Hodgkin's lymphoma were treated with a first-generation program including Adriamycin, VM 26, cyclophosphamide, and prednisone. Thirty-nine patients were under 60 years of age, and 34 were 60 years or older. The clinical and histologic characteristics of the two groups were similar. Using either univariate or multivariate analysis, age appeared as the only prognostic factor. Patients under 60 had a median survival of 48 months, with a five-year survival rate of 47 percent and a five-year disease-free survival rate for complete-remission patients of 72 percent. Patients 60 years or older had a median survival of 18 months with a five-year survival rate of 18 percent and a five-year disease-free survival rate for complete-remission patients of 24 percent. These highly significant differences were related to a non-significantly decreased complete-remission rate and a significantly higher relapse rate in elderly patients. Since patient selection according to age could play a role in the results achieved with intensive chemotherapy programs, randomized trials comparing the various chemotherapy programs for aggressive non-Hodgkin's lymphoma are warranted.

Adolescent↗
PubMed1986

Membrane ordering effects of the anticancer agent VM-26.

The effect of the anticancer agent VM-26 on acyl chain order of cellular and model membranes was examined by electron spin resonance techniques. The order parameter for the paramagnetic probe 5-doxyl stearate was increased when VM-26 was incorporated into the bilayer of fluid-phase dimyristoylphosphatidylcholine (DMPC) or gel-phase dipalmitoylphosphatidylcholine (DPPC) liposomes at concentrations up to 4.8 mol%. The ordering effect of VM-26 in DMPC was greater than that of cholesterol on an equimolar basis. The less cytotoxic congener of VM-26, VP-16, was only one-third as active as VM-26 in its ordering effects on DMPC. Higher order parameters for 5-doxyl stearate were also noted in asolectin liposomes, Ehrlich ascites tumor cells, and CCRF-CEM cells treated with VM-26. We conclude that VM-26 has significant membrane associated activity in addition to its previously recognized nuclear effects.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1984

Inhibition of the DNA catenation activity of type II topoisomerase by VP16-213 and VM26.

Studies suggest that the anticancer drugs VP16-213 and VM26 produce cytotoxicity by inducing protein-associated DNA breakage in vivo through interaction with a yet unknown nuclear component. The effects of these drugs and their congeners on topoisomerase activities was investigated. VP16-213, VM26, and congeners active toward inducing DNA breaks also inhibited the catenation activity of eukaryote type II topoisomerase in vitro at very low drug concentrations. A structure-activity relationship was obtained for inhibition of catenation that parallels in vivo DNA breakage and cytotoxic activities. Type I topoisomerase activity was totally unaffected by these drugs.

Animals↗
PubMed1986

In vivo stimulation by antitumor drugs of the topoisomerase II induced cleavage sites in c-myc protooncogene.

Several antitumor drugs including DNA intercalative and non intercalative agents induce in vitro and in vivo double-stranded DNA breaks by stabilization of a topoisomerase II-DNA complex. In order to locate cleavage sites in an actively transcribed oncogene, N417 cells, originating from a human small cell lung carcinoma and containing 45-50 copies of c-myc oncogene, were treated with mAMSA, 9 hydroxyellipticine and VM 26. The presence of DNA lesions in c-myc was investigated by Southern blot hybridization with a human c-myc probe. In addition to normal bands, DNA patterns of drug treated-cells revealed the presence of new bands most likely corresponding to topoisomerase II-mediated cleavage as these bands were not found in untreated control DNA and in DNA treated with oAMSA, a biologically inactive stereoisomer of mAMSA. Major cleavage sites induced by drugs in the N417 cell c-myc locus were located in the 5' end of the c-myc exon 1 closely to some DNAse I hypersensitive sites which are assumed to reflect an activity of the gene. Therefore our data suggest that TopoII-mediated drug activity correlates with gene activity.

Aminoacridines↗
PubMed1991

Nuclear matrix attachment regions and topoisomerase II binding and reaction sites in the vicinity of a chicken DNA replication origin.

We have mapped nuclear matrix attachment regions (MARs), defined by their specific binding to nuclear matrices in vitro, and sites of topoisomerase II reaction, detected by DNA cleavage in vitro in the presence of the inhibitor VM-26, in the vicinity of the replication origin of the chicken alpha-globin gene domain. Two MARs are located close to the downstream end (in the direction of transcription) of a 3 kb fragment which includes the origin. These MARs contain sites for strong topoisomerase II binding and reaction. Our observations on this gene domain support two hypotheses concerning MARs in eukaryotic cells, namely that they are close to DNA replication origins and that they contain multiple topoisomerase II recognition sites.

Animals↗
PubMed1994

Subcellular distribution of the alpha and beta topoisomerase II-DNA complexes stabilized by VM-26.

Studies were done to determine (a) the subcellular distribution of the alpha (170 kDa) and beta (180 kDa) isozymes of topoisomerase II, and (b) the extent to which each isozyme forms complexes with DNA in tumor cells incubated with and without VM-26. Western blotting revealed that topoisomerase II beta was highly unstable during cell fractionation. However, preincubation of human CEM leukemia cells with 5-100 microM VM-26 for 30 min protected the beta isozyme from degradation by progressively increasing the amount of this isoform bound to DNA. The amount of topoisomerase II beta detected in nuclei of CEM cells incubated for 30 min with 25 microM VM-26 was 7-fold greater than in nuclei from untreated control cells. VM-26 also had a protective effect on topoisomerase II beta in HL-60 leukemia and WiDR colon carcinoma cells. In contrast, the intercalating agents mitoxantrone and m-AMSA did not protect topoisomerase II beta from degradation during cell fractionation. The stabilization of topoisomerase II beta by VM-26 allowed subsequent studies of the subcellular distribution of the topoisomerase II isozymes. Both isozymes were detected in the nonmatrix (high salt-soluble) fraction of nuclei from CEM cells, but only topoisomerase II alpha was present in the nuclear matrix. VM-26 stabilized binding of the alpha and beta topoisomerase II isoenzymes to nonmatrix DNA and topoisomerase II alpha to matrix DNA. The differences observed in the subnuclear distribution and DNA binding pattern of the topoisomerase II isozymes support the hypotheses that each isozyme has a distinct cellular function, and that both the alpha and beta isozymes are potential targets for VM-26 in intact cells. In addition, the results demonstrated that pretreatment of various cell lines with VM-26 is a useful way to stabilize topoisomerase II beta during cell fractionation.

Amsacrine↗
PubMed1991

A new action for topoisomerase inhibitors.

Topoisomerases are known to aid DNA replication by breaking and resealing supercoiled DNA. Consequently, cells exposed to topoisomerase inhibitors before or during the S (DNA synthetic) phase of the cell cycle undergo abnormal DNA replication and become irreversibly blocked in the G2 (pre-mitosis) phase. We report that following a 4-h exposure to topoisomerase II inhibitors, murine erythroleukemic cells (MELC) do not form mitotic figures but exhibit a time-dependent progression into G2 (4N DNA) and greater than G2 (up to 8N DNA) stages of the cell cycle. Following exposure to the topoisomerase I inhibitor camptothecin, recovering MELC also exhibit greater than G2 polyploidy, but to a considerably lesser degree: mitotic figures are present and a subpopulation of cells resumes cycling. However, both topo I and topo II inhibitors induce maximal percentages of greater than G2 cells when synchronized MELC are in the G2/M phase at the time of exposure. This suggests that, in addition to their S-phase action, topoisomerase inhibitors can interfere with chromosome condensation during G2 and, in so doing, induce polyploidy.

Animals↗