Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Etoposide (VP-16) resistance is expressed following in vitro exposure of HN-1 and MCF-7 human tumor cells to the drug itself or to fractionated X irradiation. VP-16-selected sublines prove cross-resistant to Adriamycin, amsacrine and actinomycin D, whilst X-ray-pretreated sublines show cross-resistance to only actinomycin D. These differential responses, in the HN-1 series, are not associated with significant differences in amounts of immunoreactive topoisomerase (topo) II, altered topo-II catalytic activity of nuclear extracts or changes in susceptibility of the topo II to VP-16- or amsacrine-induced DNA-protein cross-link formation. Therefore significant modifications in topo II appear not to be implicated in VP-16 resistance in these HN-1 sublines.
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PMID:A lack of detectable modification of topoisomerase II activity in a series of human tumor cell lines expressing only low levels of etoposide resistance. 184 24

The usefulness of MDR1, GST-pi or topoisomerase II mRNA expression detected by dot blot analysis as an indicator of intrinsic resistance to adriamycin was investigated in 15 fresh human tumor specimens. MDR1 and GST-pi expression, which is known to be a marker for adriamycin resistance, was detected in six (66.7%) and seven (77.8%) of the nine clinically resistant tumors, respectively. However, in four of the six adriamycin responsive tumors, MDR1 and/or GST-pi expression were detected. Thus these two markers were not indicators of clinical response to adriamycin. In contrast, topoisomerase II mRNA expression was significantly correlated with clinical response (p less than 0.01, chi 2 test). The expression of topoisomerase II mRNA was detected at a high level in five (83.3%) of the 6 clinically responsive tumors, and the other nine tumors resistant to adriamycin treatment exhibited undetectable or low levels of topoisomerase II mRNA. We therefore suggest that the level of topoisomerase II mRNA expression is a useful marker of the clinical response to adriamycin.
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PMID:Expression of MDR1, GST-pi and topoisomerase II as an indicator of clinical response to adriamycin. 185 Feb 21

Recent structure-activity relationship studies emphasize the critical role of topoisomerase II-mediated DNA cleavage on the cytotoxic activity of anthracycline anti-tumor antibiotics. Such studies have also given evidence of the peculiar features of the drug interference with DNA topoisomerase II activity. In contrast to other cytotoxic topoisomerase II inhibitors (acridines, epipodophyllotoxins), anthracyclines produce persistent DNA cleavable complexes. This property is more evident with doxorubicin derivatives than with daunorubicin derivatives. The strength of DNA binding apparently does not correlate with the stimulatory effect of anthracyclines on topoisomerase II-mediated DNA cleavage and with their cytotoxic potency. However, drug intercalation is still required for optimal drug activity. Such an observation suggests that the specific mode of DNA interaction, rather than the strength of binding, is important in determining the cytotoxic potency. The extent of anthracycline-induced cleavage results from a balance between a stimulation and a suppressive effect of the drug on topoisomerase II DNA cleavage. Anthracyclines are sequence selective in the induction of DNA cleavage by purified topoisomerase II. Despite the extensive effort in developing DNA intercalating agents as anti-tumor drugs, the limited success of such an approach could be rationalized in terms of the still inadequate 'rational design', since the molecular basis of specific drug-DNA topoisomerase II interaction (e.g. sites of cleavage, cell response to DNA damage, etc.) is not completely understood. Such studies indicating structural requirements in anthracycline molecules, which are critical for specific drug interference with topoisomerase II functions, provide the opportunity to re-examine the mechanism of action of these agents and to design new, more selective derivatives.
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PMID:DNA topoisomerase II as the primary target of anti-tumor anthracyclines. 196 3

In an attempt to understand the underlying cellular/biochemical factors of sensitivity/resistance in human small-cell lung cancer (SCLC), 2 SCLC tumor lines were compared with respect to tumor responsiveness to drug treatment, cell sensitivity, cellular doxorubicin accumulation, and DNA topoisomerase-II-mediated DNA cleavage. The tumor lines growing in nude mice with similar growth characteristics (doubling time around 10 days) were selected since one (POCI tumor) was found to be hypersensitive and the other (POSG tumor) resistant to doxorubicin treatment. The pattern of anti-tumor drug response of the doxorubicin-resistant tumor was atypical (i.e., non-adherent to the well-characterized multi-drug-resistant phenotype), since it responded to vincristine. The markedly different in vivo tumor response reflected the intrinsic cellular sensitivity to doxorubicin. No correlation was found between cellular drug accumulation and doxorubicin sensitivity following in vitro exposure to the drug. In agreement with this observation, the expression of mdr-I gene was undetectable in these tumors. Thus, in the POSG tumor, resistance to doxorubicin occurred without expression of the P-glycoprotein and reduction of cellular drug accumulation. In contrast, the extent of DNA cleavage produced by doxorubicin was markedly higher in the doxorubicin-hypersensitive than in the doxorubicin-resistant tumor. These results, taken together with previous observations in SCLC cell lines, support the important role of DNA topoisomerase-mediated effects in the sensitivity of SCLC to doxorubicin.
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PMID:Relationships among tumor responsiveness, cell sensitivity, doxorubicin cellular pharmacokinetics and drug-induced DNA alterations in two human small-cell lung cancer xenografts. 197

Strategies to circumvent different forms of multidrug resistance (MDR) in tumor cells will be discussed. The form of MDR associated with overexpression of P-glycoprotein. Pgp-MDR, is well-understood, and its features are briefly described. Many clinically useful lipophilic organic bases have been shown to interfere with drug efflux mediated by Pgp, consequently circumventing or overcoming this form of MDR. Based on these empiric observations, screening and molecular modeling efforts are being employed to develop new modulators of Pgp-MDR. However, because inhibition of normal tissue Pgp can cause unacceptable toxicities, new strategies to circumvent Pgp-MDR in tumors must be sought. Possibilities range from pharmacokinetic modeling to the development of tissue-specific inhibitory antibodies or antisense oligonucleotides. Tumor cells expressing altered DNA topoisomerase II express a more restricted form of MDR, termed at-MDR, that will be discussed briefly and compared with Pgp-MDR. Modulators of Pgp-MDR are without effect in cells expressing only at-MDR. However, some analogs of anthracyclines appear to act via a topo II-independent pathway and can circumvent this form of resistance. Also, alterations in topoisomerase II may have consequences for other cellular functions, as at-MDR cells appear to have defects in DNA repair pathways, suggesting other areas for therapeutic exploitation.
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PMID:Strategies to circumvent multidrug resistance due to P-glycoprotein or to altered DNA topoisomerase II. 198 Apr 25

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.
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PMID:Etoposide with lonidamine or pentoxifylline as modulators of alkylating agent activity in vivo. 204 6

The time course of expression of topoisomerase I, topoisomerase II, and simian virus 40 (SV40) large tumor (T) antigen was determined in whole-cell extracts of uninfected versus SV40-infected TC7 cells. After a minor increase, the level of topoisomerase I remained fairly constant throughout the time course in both uninfected and SV40-infected cells. In contrast, the level of topoisomerase II increased markedly in SV40-infected cells but not in uninfected cells following the appearance of SV40 T antigen.
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PMID:Differential increase in topoisomerase II in simian virus 40-infected cells. 215 53

Streptozotocin (STZ) is a monofunctional nitrosourea employed in the treatment of patients with islet cell tumors. To analyze the role of DNA repair mechanisms in causing resistance to STZ, we evaluated the cytotoxicity by this agent in three human tumor lines that differ with respect to their abilities to repair N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) damaged virus (the Mer phenotype). HT-29, A2182, and BE human tumor lines are high, intermediate and low, respectively, with regard to features that define the Mer phenotype. Our results demonstrated that the order of resistance to STZ is HT-29 greater than A2182 greater than BE. The degree of inhibition of DNA synthesis by STZ was in the following order: BE greater than A2182 greater than HT-29. O6-Alkyltransferase activity was increased markedly in HT-29 cells compared to A2182 cells which, in turn, had significantly increased levels compared to the BE line. Other potential factors such as 3-methyladenine DNA glycosylase activity, the induction by STZ of single-stranded DNA breaks, and the kinetics of repair of these breaks do not clearly underlie differences in cytotoxicity among the three tumor lines. However, increased topoisomerase II activity, as well as enhanced sensitivity to agents that interact with topoisomerase II, was present in A2182 cells compared to BE cells. These findings demonstrate that while O6-alkyltransferase contributes to resistance to STZ in some Mer+ tumor lines, other mechanisms may also contribute to resistance to this agent.
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PMID:Mechanisms underlying resistance to streptozotocin in Mer+ and Mer- human tumor lines. 215 17

A combination of tumor necrosis factor (TNF) and the topoisomerase I inhibitor, camptothecin, or the topoisomerase II inhibitors, teniposide and amsacrine, produced dose-dependent synergistic cytotoxicity against the murine L929 fibrosarcoma cells. Similar synergy was not observed with a combination of TNF and bleomycin. To define the role of TNF in the augmentation of tumor cell killing by topoisomerase I or II inhibitors, the effect of TNF on the production of enzyme-linked DNA strand breaks induced in cells by topoisomerase inhibitors was investigated. L929 cells incubated for 1 h with the topoisomerase inhibitors contained protein-linked strand breaks. In contrast, TNF alone did not induce DNA strand breakage. However, when cells were incubated simultaneously with TNF and camptothecin, amsacrine, Adriamycin, actinomycin D, teniposide, or etoposide, increased numbers of strand breaks were produced. Preincubation of the cells with TNF for 30 min or 3 h before the addition of camptothecin or etoposide resulted in no more strand breaks than that observed in cells incubated with the drugs alone. TNF treatment of L929 cells produced a rapid and transient increase in specific activity of extractable topoisomerases I and II. These increases were maximum at 2-5 min of TNF treatment and by 30 min the activities of extractable enzymes were equal to or less than those detected in extracts from untreated cell controls. The transient nature of the increase in extractable topoisomerase activity may explain the kinetics and significance of the order of addition of TNF and inhibitors for maximal synergistic activity. These data are consistent also with a role for topoisomerase-linked DNA lesions in the TNF-mediated potentiation of killing of L929 cells by topoisomerase inhibitors.
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PMID:Potentiation of topoisomerase inhibitor-induced DNA strand breakage and cytotoxicity by tumor necrosis factor: enhancement of topoisomerase activity as a mechanism of potentiation. 215 96

The enzymes involved in the regulation of the three-dimensional structure of DNA, topoisomerase I and II, are important for the handling of DNA during vital cellular processes such as translation, transcription and mitosis. The enzymes are currently being studied intensively, they are being biochemically characterized and their mechanism of action is now better understood. Empirically discovered antitumor drugs appear to interfere with these enzymes, especially topoisomerase II. The DNA-topoisomerase II complex, which is an intermediate in the normal enzyme pathway, is stabilized by the drug and forms a 'cleavable complex', which appears to be cytotoxic. The drugs involved are, e.g. anthracyclines, epipodophyllotoxins and acridines. The central role of this enzyme offers the cell an opportunity for the development of resistance by down-regulation of this enzyme or the production of resistant mutants, provided the adaptation does not hamper other vital cell functions. Knowledge of the working mechanism and the cellular regulation of the topoisomerases might lead to the selection of most effective drugs and treatment schedules, and to circumvention of drug resistance.
Med Oncol Tumor Pharmacother 1990
PMID:Topoisomerases, new targets in cancer chemotherapy. 216 32


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