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

---

Query: EC:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of high-dose etoposide in the initial treatment of newly diagnosed adult ALL was assessed in a combined clinical and laboratory study. Therapy on protocol JH8802 consisted of two induction modules, module 1 containing prednisone, vincristine, high-dose etoposide and L-asparaginase (L-asp), followed by module 2 containing cytarabine (Ara-C) and daunorubicin (DNR). Patients achieving a complete remission (CR) underwent bone marrow transplantation (BMT) or intensive maintenance therapy. Results were compared to the preceding protocol (JH8302), which was similar except for omission of etoposide and L-asp. The CR rate following module 1 was 45% on protocol JH8802 and 9% on protocol JH8302 (p < 0.0002). Nonetheless, the two protocols had similar CR rates following module 2 (69% on protocol JH8302; 77% on JH8802) and indistinguishable survivals. Laboratory investigations performed on blasts harvested prior to chemotherapy revealed two factors that could potentially contribute to decreased etoposide sensitivity in ALL blasts. A flow microfluorimetry-based assay of nuclear DNR accumulation detected small P-glycoprotein (Pgp)-mediated decreases in drug accumulation in a quarter of the samples. Western blotting demonstrated that topoisomerase II was present in all samples but was diminished in amount compared to the Molt3 human ALL cell line. Immunoperoxidase staining with affinity-purified antibodies revealed that topo II alpha, the target for etoposide, was detectable in only a minority of the blasts (median 7.5%, range < 1-35%) at diagnosis. These observations raise the possibility that alterations in drug accumulation and diminished target enzyme levels might both limit the long-term efficacy of a single course of high dose etoposide administered early in the treatment of adult ALL.
Leuk Lymphoma 1996 Sep
PMID:Addition of etoposide to initial therapy of adult acute lymphoblastic leukemia: a combined clinical and laboratory study. 902 88

Drug resistance often results in failure of anticancer chemotherapy in leukemias. Several mechanisms of drug resistance are known with multidrug resistance (MDR) being the best characterized one. MDR can be due to enhanced expression of certain genes (MDR1, MRP or LRP), alterations in glutathione-S-transferase activity or GSH levels and to reduction of the amount or the activity of topoisomerase II. Here we review the current status of the clinical significance of the various mechanisms of MDR in leukemias and also discuss possibilities for the reversal of MDR. MDR1 gene expression has been seen in many leukemias, notably in acute myeloid leukemia (AML) and blast crisis of chronic myeloid leukemia. Both MDR1 RNA and P-glycoprotein expression of the leukemic cells have been shown to correlate with poor clinical outcome in AML. However, preliminary results indicate that the MRP gene as well as the LRP gene can be expressed in AML. Thus, drug resistance in leukemias appears to be multifactorial. P-glycoprotein-mediated MDR can be reversed by several drugs. These resistance modifiers are currently evaluated with regard to their clinical efficacy. Despite some encouraging results, reversal of drug resistance and subsequent improvement in clinical outcome remains to be shown.
Leuk Lymphoma 1996 Nov
PMID:Multidrug resistance in leukemias and its reversal. 903 Oct 75

In mammalian cells, there are two isoforms of DNA topoisomerase II, designated alpha (170-kDa form) and beta (180-kDa form). Previous studies using cell lines have shown that the topoisomerase IIalpha and beta isoforms are differentially regulated during the cell cycle and in response to changes in growth state. Moreover, both isoforms can act as targets for a range of anti-tumour drugs. Here, we have analysed the normal tissue distribution in humans of topoisomerase IIalpha and beta using isoform-specific antibodies. In addition, we have studied expression of these isoforms in 69 primary tumour biopsies, representative either of tumours that are responsive to topoisomerase II-targeting drugs (breast, lung, lymphoma and seminoma) or of those that show de novo drug resistance (colon). Topoisomerase IIalpha was expressed exclusively in the proliferating compartments of all normal tissues, and was detectable in both the cell nucleus and cytoplasm. In biologically aggressive or rapidly proliferating tumours (e.g. high-grade lymphomas and seminomas), there was a high level of topoisomerase IIalpha, although expression was still detectable in colon tumours, indicating that expression of this isoform is not sufficient to explain the intrinsic drug resistance of colon tumours. Topoisomerase IIbeta was expressed ubiquitously in vivo and was localized in both the nucleoli and the nucleoplasm. This isoform was present in quiescent cell populations, but was expressed at a generally higher level in all tumours and proliferating cells than in normal quiescent tissues. We conclude that topoisomerase IIalpha is a strict proliferation marker in normal and neoplastic cells in vivo, but that topoisomerase IIbeta has a much more general cell and tissue distribution than has topoisomerase IIalpha. The apparent up-regulation of topoisomerase IIbeta in neoplastic cells has implications for the response of patients to anti-tumour therapies that include topoisomerase II-targeting drugs.
...
PMID:The distribution and expression of the two isoforms of DNA topoisomerase II in normal and neoplastic human tissues. 915 56

Secondary therapy-related, acute lymphoblastic leukemia (S-ALL) is less common than its myeloblastic counterpart. S-ALL with MLL gene rearrangements have only been reported on six previous occasions. Only three of these had t(4;11)(q21;23) S-ALL with MLL-AF4 fusion transcript has only been reported in one earlier case. In this report a rare case of S-ALL with MLL-AF4 transcript is described in a 36 year old woman treated for breast carcinoma with chemotherapy which included the topoisomerase II inhibitor, VP-16. The precise incidence of MLL gene rearrangement in S-ALL still remains to be clarified.
Leuk Lymphoma 1997 Apr
PMID:Translocation t(4;11)(q21;q23) and MLL gene rearrangement in acute lymphoblastic leukemia secondary to anti topoisomerase II anticancer agents. 916 51

Etoposide, a topoisomerase II inhibitor, is a chemotherapeutic agent that is used in the treatment of a wide variety of neoplasms, including small cell lung cancer, germ cell cancer, testicular cancer, acute leukemia, and lymphoma. Although it has proven valuable, etoposide is also a known mutagen and has been implicated as a causative agent of treatment-related secondary acute nonlymphocytic leukemia. We have investigated the induction of mutation following etoposide treatment in vivo using the hypoxanthine phosphoribosyltransferase (hprt) T-cell cloning assay in small cell lung cancer patients receiving single-drug etoposide chemotherapy. This report presents results on the monitoring of 12 patients (mean age, 74.8 +/- 6.0 years; range, 66-83 years) before, during, and after chemotherapy. The treatment regimen included up to six cycles of oral etoposide given in twice-daily 50-mg tablets for 10-14 days, separated by 2 weeks of rest. Peripheral blood samples were collected on the first day of each cycle prior to treatment. Patients received one to six etoposide cycles and were followed for 0.7-5.3 months after the start of chemotherapy (total etoposide dose, 1.4-8.4 g). Results from the pooled data show no significant increase in the hprt mutant frequency (pretreatment, 46 x 10(-6) +/- 38 x 10(-6), versus posttreatment, 55 x 10(-6) +/- 46 x 10(-6)), although considerable interpatient variability was observed. Of a total of 424 selected mutants, 228 were analyzed by sequencing hprt cDNA. Spectra of 56 pretreatment and 147 posttreatment mutations revealed significant enhancement of AT-->TA transversions and a concomitant decrease in the number of GC-->TA transversions in posttreatment spectra, when they were compared with pretreatment or control spectra. No evidence for the induction of gross deletions or rearrangements was found in the spectra of mutants that were recovered from patients after etoposide treatment. The lack of enhanced mutant frequency after treatment suggests that the etoposide chemotherapy was not particularly effective in inducing mutation, as measured by the hprt assay. It is proposed that mutated cells are eliminated through apoptosis due to accumulated DNA damage.
...
PMID:Mutation frequency and spectrum in lymphocytes of small cell lung cancer patients receiving etoposide chemotherapy. 933 Nov 3

Lymphoid lineage tumor cells differ widely in their relative sensitivity or resistance to the induction of apoptosis by a variety of chemotherapeutic drugs. We used a model system of virally transformed B- and T-lymphoma cell lines to show that avian T-lymphoma cells are highly resistant, whereas B-lymphoma cells are highly sensitive, to the induction of apoptosis by a wide spectrum of chemotherapeutic drugs that induce different types of lesions in DNA. Among the various drugs examined, the topoisomerase inhibitors, camptothecin, actinomycin D, and etoposide, were the most potent inducers of apoptosis. Examination of the relative contribution of DNA replication and transcriptional inhibition to the differential induction of apoptosis by the topoisomerase inhibitors revealed that the signals initiating the apoptotic response vary, even among compounds with similar cellular targets. Specifically, DNA replication plays a major role in the induction of camptothecin-induced apoptosis, and a lesser role in the induction of apoptosis by etoposide. In contrast, DNA replication is not involved in the induction of apoptosis by actinomycin D. Transcriptional inhibition may provide the major cellular signal for apoptosis induction by this compound. In addition, we determined that the extent of topoisomerase I-cleavable complex inhibition is similar even in genes that are transcribed at different levels and by different RNA polymerases. An overexpressed c-myc gene is no more vulnerable to topoisomerase inhibition than its normally expressed counterpart. In contrast, even under conditions yielding similar amounts of topoisomerase inhibition, rRNA genes are more sensitive to transcriptional inhibition than are the c-myc genes.
...
PMID:Contribution of gene-specific lesions, DNA-replication-associated damage, and subsequent transcriptional inhibition in topoisomerase inhibitor-mediated apoptosis in lymphoma cells. 945 68

We had reported that the plant-derived 1,8-dihydroxyanthraquinone derivatives, emodin and danthron, were clearly genotoxic in mouse lymphoma L5178Y cells, whereas chrysophanol was only weakly genotoxic and physcion not at all. Danthron was more potent than emodin. Furthermore, we had found that these compounds bound non-covalently to DNA and inhibited topoisomerase II activity. Interestingly, in these systems emodin was more potent than danthron. This inversion of the ranking prompted us to investigate the underlying mechanism. Since emodin shows a high serum-protein binding affinity, horse serum used as a media-supplement in the mouse lymphoma genotoxicity assays was analyzed for a potential selective scavenging of emodin. Non-covalent DNA-binding in mouse lymphoma L5178Y cells was investigated in the absence or presence of serum. In the presence of 10% serum, the DNA-binding potency of emodin was markedly reduced and was lower than that of danthron. We also applied mutation assays with mouse lymphoma cells and AS52 cells and varied the serum concentration used. In the absence of serum emodin showed slightly higher mutagenicity in AS52 cells than danthron. At reduced serum concentration (0.5%) emodin was strongly cytotoxic to the mouse lymphoma cells. For chrysophanol and physcion, a considerable reduction of the non-covalent DNA-binding potency in intact cells was found when compared to danthron, in concordance with their lower genotoxic potency. Overall, these data support the understanding that the genotoxicity of anthraquinones is, at least in part, mediated by non-covalent DNA-binding.
...
PMID:Factors affecting the genotoxic potency ranking of natural anthraquinones in mammalian cell culture systems. 963 May 66

A 59-year-old female suffering from malignant lymphoma developed therapy-related acute myeloblastic leukemia (t-AML) after chemotherapy consisting of treatment with DNA-topoisomerase II inhibitors, etoposide and mitoxantrone, and an alkylating agent, cyclophosphamide. The cumulative dose of etoposide administration was 5500 mg; 1500 mg given intravenously and 4000 mg orally. One year later, she suddenly developed AML of FAB M2. Cytogenetic analysis of bone marrow cells revealed deletion of 7q and a rare translocation, t(16;21)(q24;q22). Southern blot analysis of bone marrow cells did not detect rearrangement of the AML1 gene, however, fluorescence in situ hybridization (FISH) analysis of bone marrow cells at interphase and metaphase revealed a translocational splitting between chromosome 21 involving AML1 gene and chromosome 16. These results suggest that the breakpoint is not located in the breakpoint cluster region for t(8;21). The patient was treated with chemotherapy and entered complete remission.
...
PMID:A case of therapy-related acute myeloblastic leukemia with t(16;21)(q24;q22) after chemotherapy with DNA-topoisomerase II inhibitors, etoposide and mitoxantrone, and the alkylating agent, cyclophosphamide. 963 85

A number of recent studies have investigated the expression of topoisomerase II in clinical leukemia specimens. Here we outline the rationale for these studies, identify potential pitfalls, summarize recent results, and discuss unanswered questions in this area.
Leuk Lymphoma 1998 Apr
PMID:Topoisomerase II and the response to antileukemic therapy. 968 21

We recently cloned the cDNA TIS (topoisomerase inhibitor-suppressed) in RVC lymphoma cells exposed to the topoisomerase inhibitors. To elucidate the suppression mechanism of the TIS mRNA by camptothecin, we characterized the structures of the TIS gene. The gene spanned about 21 kb including 11 exons and was present as a single copy. The putative transcription site was present 192 bp upstream from the ATG codon. The typical TATA sequence and CCAAT promoter element were located at positions -21 and -81, respectively. The unidirectional deletion analysis of the 5'-flanking region revealed that [-132/+160] is the promoter region, which participates in the responsiveness to camptothecin. A Northern blot analysis showed that the TIS was expressed in most mouse tissues; at the highest level in the liver and to less extent in the heart and skeletal muscle. The present study showed that the expression of the TIS is suppressed at the transcriptional level by camptothecin. Considering that topoisomerase I is an essential enzyme in mammalian cells, the TIS protein may have an important role in camptothecin toxicity.
...
PMID:Cloning of the TIS gene suppressed by topoisomerase inhibitors. 971 45


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---