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)

Etoposide, a semisynthetic derivative of podophyllotoxin, is increasingly used to treat cancer. Etoposide is a phase-specific, cytotoxic drug acting in the late S and early G2 phases of the cell cycle. It appears to cause breaks in DNA by either an interaction with DNA-topoisomerase II or the formation of free radicals. Most studies show a biexponential decay after the intravenous (IV) administration of etoposide. The peak plasma concentrations of drug and the area under the concentration versus time curve (AUC) are linearly related to the IV dose. Considerable interpatient variability of pharmacokinetic variables exists after IV etoposide. Various metabolites of etoposide have been identified, but their detection and quantitation are disputed. Approximately 30% to 70% of an etoposide dose is excreted. The bioavailability of oral etoposide is approximately 50%, but its absorption is not linear with increasing doses within the range in clinical use. Considerable interpatient and intrapatient variability exists in the pharmacokinetics of oral etoposide. There is no evidence of etoposide accumulation after multiple consecutive doses by either the IV or oral route. The exact roles of the liver and kidney in metabolism and excretion of etoposide are uncertain. Etoposide has been shown to be a highly schedule-dependent drug in clinical studies. This, together with the phase-specific action of etoposide and its increasingly widespread use in treating cancer, makes the clinical pharmacology of this drug of great clinical importance.
...
PMID:The clinical pharmacology of etoposide. 198 35

In an effort to improve the additive anti-tumor efficacy of commonly used alkylating agents, the topoisomerase-II inhibitor etoposide was used in combination with either the mitochondrial poison and energy-depleting agent lonidamine or the hemorheologic agent and tumor-blood-flow-increasing agent pentoxifylline. In the FSaIIC murine fibrosarcoma system, these modulators were evaluated for modulation of whole-tumor cell killing vs. bone-marrow CFU-GM toxicity with the alkylating drugs CDDP, CTX, L-PAM or BCNU. Etoposide alone was essentially additive with the alkylating drugs for both tumor-cell and bone-marrow killing, except for BCNU, where a substantial increase in tumor-cell killing occurred (0.5 to 2.0 logs over the dose range of BCNU tested) without a significant increase in bone-marrow toxicity. Etoposide plus lonidamine was significantly more active than etoposide alone only with CTX and BCNU in tumor-cell vs. bone-marrow killing. Etoposide plus pentoxifylline was also most active with these two alkylating agents, where increases in tumor-cell killing of 0.5 to 1.0 log were observed. Hoechst-33342-defined tumor-cell sub-population studies revealed that etoposide significantly improved the killing of dim (putative hypoxic) cells by CDDP, but neither lonidamine nor pentoxifylline significantly improved killing of bright or dim cells together. With CTX, etoposide plus lonidamine or pentoxifylline substantially improved killing of dim cells over etoposide alone (each by about 0.8 logs). These data indicate that a therapeutic advantage may be achievable by combining etoposide with lonidamine or pentoxifylline for use with alkylating drugs.
...
PMID:Etoposide with lonidamine or pentoxifylline as modulators of alkylating agent activity in vivo. 204 6

Etoposide is known to inhibit the activity of topoisomerase II, and to possess radiosensitizing effects. In this paper we show that pretreatment of mice with etoposide one day before whole-body irradiation had a protective effect against radiation-induced bone marrow death. The LD50/30 of mice given radiation alone was 8.26 Gy while that of mice given etoposide one day before whole-body irradiation was 10.35 Gy. The number of endogenous colony-forming units surviving in whole body-irradiated mice was significantly increased by pretreatment with etoposide.
...
PMID:Etoposide protects mice from radiation-induced bone marrow death. 211 Jan 26

Etoposide (VP-16) and several other unrelated anti-tumour agents appear to act by inhibiting the enzyme DNA topoisomerase II. We report here the development and characterization of an etoposide-resistant human leukaemic CCRF-CEM cell line, CEM/VP-1. The cell line was 15-fold more resistant to etoposide than the parental CEM cells and exhibited cross-resistance to other topoisomerase II inhibitors including teniposide, m-AMSA, and doxorubicin. CEM/VP-1 cells exhibited only a low level cross-resistance to the Vinca alkaloids, vinblastine and vincristine, known inhibitors of mitotic spindle formation. As a first step in defining the mechanism of resistance to etoposide, we compared the levels of topoisomerase II activity and its drug sensitivity in nuclear extracts from the resistant and sensitive CEM cells. As determined by a kinetoplast DNA decatenation assay, the level of DNA topoisomerase II activity in CEM/VP-1 nuclear extracts was approximately 2-fold lower than that in CEM cells, and the activity appeared to be resistant to inhibition by etoposide. Furthermore, the DNA topoisomerase II activity in CEM/VP-1 nuclear extracts did not promote the etoposide-dependent cleavage of pBR322 DNA observed with extract from sensitive cells. These results suggest that etoposide resistance in the CEM/VP-1 cell line may at least in part be due to an altered topoisomerase II, or associated factor, resulting in a reduced ability to induce DNA cleavage in the presence of drug.
...
PMID:Development and properties of an etoposide-resistant human leukaemic CCRF-CEM cell line. 215 15

Four drugs known to interact with topoisomerase II were assessed for their ability to enhance the cytotoxicity of cis-diamminedichloroplatinum(II) (CDDP) in Chinese hamster ovary (CHO) cell lines sensitive and resistant to VM-26. The combination treatments were analyzed by isobologram methodology. On 24 h exposure, there was no significant difference in the cytotoxicity of novobiocin or ciprofloxacin toward either cell line. The resistant cells were approximately 9-fold more resistant to 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) and approximately 170-fold more resistant to etoposide after a 24-h exposure. The combination of novobiocin and cisplatin produced greater than additive cell kill over the entire dose range of cisplatin tested in both cell lines. m-AMSA and CDDP produced cell kill that fell within the envelope of additivity. Etoposide and CDDP resulted in cytotoxicity that was slightly greater than additive at low CDDP concentrations and additive at the highest concentration of CDDP tested in the parental cell line and was slightly greater than additive in the resistant cell line. Ciprofloxacin and CDDP, like novobiocin, resulted in greater than additive cell kill in both cell lines. The enhancement of CDDP cytotoxicity by novobiocin that was seen in exponentially growing cells was lost in stationary-phase cultures. In these studies, novobiocin and, to a lesser degree, ciprofloxacin produced greater than additive cell kill in combination with CDDP in parental and epipodophyllotoxin-resistant CHO cells.
...
PMID:Ability of four potential topoisomerase II inhibitors to enhance the cytotoxicity of cis-diamminedichloroplatinum (II) in Chinese hamster ovary cells and in an epipodophyllotoxin-resistant subline. 217 96

Etoposide and teniposide are semi-synthetic glucoside derivatives of podophyllotoxin with a documented anti-tumour activity in various types of malignant diseases. It was an early observation that these epiphodophyllotoxins were efficacious in hematological malignancies such as lymphomas and leukemias. In this report the clinical evidence supporting the activity of etoposide and teniposide in acute lymphoblastic (ALL) and non-lymphoblastic leukemia (ANLL) is reviewed. Unlike podophyllotoxin, etoposide and teniposide do not appear to affect microtubular function nor arrest cells in mitosis. These epiphodophyllotoxins, like other DNA intercalating agents, have topoisomerase II as their target. Most studies with etoposide have been performed in ANLL and with teniposide in ALL. This choice seems to be rather arbitrary and is better explained by traditional reasons than actual study results. The data in acute leukemias are partly flawed by the absence of certain prospective comparative trials. However, the current information on etoposide clearly shows that this agent has substantial activity in ANLL and may well be incorporated into front-line regimens and the same is true for teniposide in the treatment of ALL. Nevertheless, based on available literature, there are no convincing data to the author's mind to support that one of these agents is superior to the other in the treatment of acute leukemias.
...
PMID:Etoposide and teniposide in the treatment of acute leukemia. 218 20

Several podophyllotoxin-related lignans have been shown to possess significant antifungal activity against a number of filamentous fungi. Initial structure-activity studies indicate this action is sensitive to change at the 4 and 4' positions of the podophyllotoxin skeleton. Good correlation has been observed between antifungal action and the ability to inhibit the relaxation of supercoiled plasmid DNA by a topoisomerase II preparation from Saccharomyces cerevisiae. Etoposide, an inhibitor of mammalian topoisomerase II, is inactive against this yeast enzyme, although good inhibition is shown by amiloride, 4'-(9-acridinylamino)-methanesulphon-m-anisidide (m-AMSA) and novobiocin, known inhibitors of the mammalian enzyme.
...
PMID:Topoisomerase II: a potential target for novel antifungal agents. 254 Jul 47

We have found that blockade of the Na+,K+-pump by the cardiac glycoside ouabain protects human A549 and hamster V79 cells from the cytotoxic effects of the topoisomerase II poison etoposide. One thousand-fold higher concentrations of ouabain were required to protect V79 cells compared to A549 cells. Since this difference parallels previously measured differences in pump sensitivity, it suggests that protection is mediated directly through pump blockade. Ouabain affected neither the cellular influx nor efflux of etoposide. However, pump blockade did decrease the formation of etoposide-induced DNA-topoisomerase, II-cleavable complexes, assessed as single and double strand DNA breaks using alkaline and neutral elution. To determine if this decrease were a direct effect of change in ionic environment produced by pump blockade, experiments with isolated nuclei and partially purified topoisomerase II were performed. Etoposide-induced cleavable complex formation and topoisomerase-mediated decatenation were assessed in buffers which mimicked either normal intracellular ionic conditions or those produced by ouabain. Compared to the buffer which resembled the normal intracellular ionic conditions, the buffer that mimicked the conditions produced by pump blockade produced fewer etoposide-mediated cleavable complexes in isolated nuclei and less decatenating activity of partially purified topoisomerase II. These findings demonstrate that inhibition of the Na+,K+-pump causes an alteration in the intracellular ionic environment which decreases the activity of topoisomerase II, thus producing a decrease in etoposide-induced cleavable complex formation and cytotoxicity. Since ionic changes occur inside normal cells during progression through the cell cycle as well as in cells that have undergone transformation, these data suggest that the intracellular ionic environment plays a role in determining the sensitivity of normal and malignant cells to this group of chemotherapeutic agents.
...
PMID:Dependence of etoposide-induced cytotoxicity and topoisomerase II-mediated DNA strand breakage on the intracellular ionic environment. 254 16

The cytotoxicity and DNA damage induced by the epipodophyllotoxins and several intercalating agents appear to be mediated by DNA topoisomerase II. We have purified topoisomerase II to homogeneity both from an epipodophyllotoxin-resistant Chinese hamster ovary cell line, VpmR-5, and from the wild-type parental cell line. Immunoblots demonstrate similar topoisomerase II content in these two cell lines. The purified enzymes are dissimilar in that DNA cleavage by VpmR-5 topoisomerase II is not stimulated by VP-16 or m-AMSA. Furthermore, the VpmR-5 enzyme is unstable at 37 degrees C. Thus, the drug resistance of VpmR-5 cells appears to result from the presence of an altered topoisomerase II in these cells. Purified topoisomerase II from VPMR-5 and wild-type cells has the same monomeric molecular mass as well as equivalent catalytic activity with respect to decatenation of kinetoplast DNA. Etoposide (VP-16) inhibits the activity of both enzymes. Noncovalent DNA-enzyme complex formation, assayed by nitrocellulose filter binding, is also similar, as is protection from salt dissociation of this complex by ATP and VP-16. The data suggest a model in which the drug-resistant cell line, VpmR-5, has religation activity which is less affected by drug than that of the wild-type cells. Drug effect on DNA religation and catalytic activity are dissociated mechanistically. In addition, under certain circumstances, the "cleavable complex" observed following denaturation of a drug-stabilized DNA-enzyme complex may not adequately reflect the nature of the antecedent lesion.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Purification and characterization of an altered topoisomerase II from a drug-resistant Chinese hamster ovary cell line. 255 59

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and pharmacodynamics of etoposide are reviewed. Etoposide, although similar in chemical structure to podophyllotoxin, has a different mechanism of cytotoxicity compared with its parent compound. Etoposide may stabilize type II topoisomerase-DNA complexes, preventing rejoining of single- and double-strand DNA breaks. Etoposide may also require cellular activation into intermediates, which then bind to DNA and disrupt cellular function. Oral etoposide has an average bioavailability of 50% (range, 17%-137%), with substantial intrapatient and interpatient variability. Etoposide is widely distributed in the body and is highly bound to plasma proteins (greater than 95%). Approximately 50% (range, 20%-81%) of an etoposide dose is recovered in the urine as parent drug or glucuronide, with the remainder of the dose being unaccounted for. The disposition of etoposide in patients with renal and hepatic dysfunction is discussed. Etoposide is effective in combination with other agents against lung cancer, and response rates of 90% in small-cell lung cancer have been observed. When etoposide is used in combination with other agents, response rates of approximately 80% have been observed in patients with testicular cancer. The activity of etoposide in treating leukemia, lymphoma, and breast and ovarian carcinomas and other tumors is discussed. The impact of etoposide on prolonging survival in lung and testicular cancer is addressed, and studies evaluating the pharmacodynamics of etoposide are described. Adverse effects associated with etoposide therapy include myelosuppression, alopecia, nausea and vomiting, mucositis, and hypotension after rapid intravenous administration. Etoposide has demonstrated considerable clinical efficacy against a broad spectrum of tumors.
...
PMID:Etoposide: an update. 279 80


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

---