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

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Query: EC:5.99.1.3 (topoisomerase)
9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The feasibility of combined studies on a cell-line panel and primary cultures of patient tumor cells in the preclinical evaluation of new anticancer drugs was evaluated in a study of the activity and cross-resistance pattern in vitro of the new semi-synthetic vinca alkaloid vinorelbine (Vrb). The activity of Vrb was investigated in ten cell lines representing different resistance mechanisms and in a total of 256 fresh human tumor samples, using the fluorometric microculture cytotoxicity assay (FMCA). Resistance to Vrb in the cell lines was associated with expression of the multidrug resistance-mediating P-glycoprotein and the multidrug resistance-associated protein (MRP) and by a recently described tubulin-associated mechanism, while the cell lines with topoisomerase II- and glutathion-associated resistance did not show decreased sensitivity to the drug. Cross-resistance to vincristine (Vcr) and other tubulin-active agents was high in cell lines as well as in patient cells. As with most commonly used anti-cancer drugs, Vrb was more active in hematological than in solid tumor samples. Among the solid tumors investigated, the highest in vitro response rates were observed in ovarian cancer (27%), sarcoma (25%), non-small cell lung cancer (21%) and bladder cancer (20%), while no response was observed in renal or colorectal cancer. Compared to Vcr, Vrb appeared to be slightly more active in solid tumors and slightly less active in hematological tumors. The results show that although Vrb displays a high degree of cross-resistance to Vcr and other tubulin-active drugs, some difference in the activity spectrum could be detected and that the drug is sensitive to multiple mechanisms of resistance. The results also suggest that leukemias, ovarian cancer, sarcoma and bladder cancer are possible further targets for Vrb. The combination of studies on a cell-line panel and patient tumor cells from a broad spectrum of diagnoses to evaluate a new drug seems feasible and may give information on the mechanism of action and target diagnoses for phase II trials.
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PMID:In vitro evaluation of new anticancer drugs, exemplified by vinorelbine, using the fluorometric microculture cytotoxicity assay on human tumor cell lines and patient biopsy cells. 941 16

We have established ten transplantable human soft-tissue sarcoma (STS) xenografts grown as subcutaneous tumours in the nude mouse. Nine xenografts originated from patients that needed chemotherapy in the course of their disease. The xenografts were tested for their sensitivity to maximum tolerated doses of five anti-cancer agents. Growth of treated tumours was expressed as a percentage of control tumour growth and a growth inhibition > 75% was measured for doxorubicin in 20% of the STS xenografts, for cyclophosphamide in 30%, for ifosfamide in 20%, for vincristine in 20%, whereas etoposide was not effective in the STS xenografts. In three out of ten STS xenografts MDR1 mRNA was detectable, but this was not related to the resistance against doxorubicin, vincristine or etoposide. Topoisomerase IIalpha mRNA expression levels did not reflect sensitivity to doxorubicin or etoposide. In all STS tissues, however, these levels were lower than topoisomerase IIalpha mRNA in a drug-sensitive human ovarian cancer xenograft. Glutathione concentrations and the activities of glutathione S-transferase, glutathione peroxidase and glutathione reductase were not related to resistance against the alkylating agents or doxorubicin. Of interest, in all STS tissues, glutathione S-transferase pi was the predominant isoenzyme present. In conclusion, chemosensitivity of the STS xenografts reflects clinical response rates in phase II trials on the same compounds in adult STS patients. Relatively low levels of topoisomerase IIalpha mRNA may partly account for intrinsic resistance against, for example, doxorubicin. Additional factors must contribute to moderate responsiveness to alkylating agents.
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PMID:Characterization of human soft-tissue sarcoma xenografts for use in secondary drug screening. 986 68

We examined the effect of overexpression of p21(waf1) on cytotoxicity of paclitaxel, a microtubule stabilizer, using a tetracycline-inducible expression system in human sarcoma cells (SaOs-2) that lack both functional retinoblastoma protein and p53. Under normal growth conditions, p21(waf1) is not detectable in SaOs-2 cells. Upon p21(waf1) induction by tetracycline withdrawal, we observed a reduced apoptotic response to paclitaxel with a 3- to 6-fold increase in IC50 values compared with that of cells not induced by p21(waf1). We also observed a 5-fold increase in the IC50 value when cytotoxicity to vincristine, another microtubule-disrupting agent, was assessed, whereas we observed a marked decrease in the IC50 value after p21(waf1) induction in response to etoposide, a topoisomerase II inhibitor. After treatment with paclitaxel, less accumulation of G2-M was observed in p21(waf1)-induced cells compared with non-p21(waf1)-induced cells (57% versus 74%). p21(waf1) induction also inhibited the increased cyclin B1-associated kinase activity induced by paclitaxel. Overexpression of p21(waf1) in SaOs-2 cells lacking both p53 and functional retinoblastoma protein may decrease the G2-M arrest induced by paclitaxel due to suppression of the S-G2 checkpoint, resulting in a decreased apoptotic response of cells to paclitaxel.
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PMID:Overexpression of p21(waf1) decreases G2-M arrest and apoptosis induced by paclitaxel in human sarcoma cells lacking both p53 and functional Rb protein. 1034 52

Deoxynybomycin was identified as an inducer of p21the/WAF1 gene following screening using a reporter, p21/luciferase. The present study examined its anti-proliferative effect on human tumor cell lines. Deoxynybomycin selectively inhibited growth of human osteoblastic sarcoma Saos-2, gastric cancer TMK-1, and monocytic leukemia THP-1 cells, but did not affect survival of normal human fibroblasts at doses up to 5 microg/ml. Results from an assay system using a panel of 39 human cancer cell lines indicated that deoxynybomycin has selective cytotoxic activity against lung carcinoma cell lines. Deoxynybomycin induced apoptosis in Saos-2, TMK-1, and THP-1 cells as revealed by DNA fragmentation and TUNEL assays. It inhibited topoisomerase I but not topoisomerase II. These results suggest that deoxynybomycin may be useful in cancer chemotherapy.
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PMID:Deoxynybomycin is a selective anti-tumor agent inducing apoptosis and inhibiting topoisomerase I. 1099

Recently, it has been demonstrated that Etoposide, a topoisomerase II inhibitor, can induce apoptosis in MDM2-overexpressing tumor cells by inhibition of MDM2 synthesis. We have previously shown that E2F-1 overexpression induces apoptosis of MDM2-overexpressing sarcoma cells, which is related to the inhibition of MDM2 expression. Therefore, the present study was designed to investigate the in vitro and in vivo effect of combined treatment of adenovirus-mediated E2F-1 and topoisomerase II inhibitors on the growth inhibition and apoptosis in human sarcoma cells. Two human sarcoma cell lines, OsACL and U2OS, were treated with topoisomerase II inhibitors (Etoposide and Adriamycin), alone or in combination with adenoviral vectors expressing beta-galactosidase (Ad-LacZ) or E2F-1 (Ad-E2F-1). E2F-1 expression was confirmed by Western blot analysis. Ad-E2F-1 gene transfer at a low dose (multiplicity of infection, 2) markedly increased the sensitivity of human sarcoma cells to topoisomerase II inhibitor treatment. This cooperative effect of E2F-1 and topoisomerase II inhibitors was less marked in SAOS-2 cells (p53 and pRb null). Topoisomerase II inhibitors also cooperated with E2F-1 overexpression to enhance tumor cell killing in an in vivo model using xenografts in nude mice. When combined with Adriamycin or Etoposide, E2F-1 adenovirus therapy resulted in approximately 95% and 85% decrease in tumor size, respectively, compared to controls (P<.05). These results suggest a new chemosensitization strategy that is effective in MDM2-overexpressing tumors and may have clinical utility.
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PMID:Additive effect of adenovirus-mediated E2F-1 gene transfer and topoisomerase II inhibitors on apoptosis in human osteosarcoma cells. 1139 76

Aqueous extract of Phyllanthus amarus (P. amarus) treatment exhibited potent anticarcinogenic activity against 20-methylcholanthrene (20-MC) induced sarcoma development and increased the survival of tumour harboring mice. The extract administration (p.o) was also found to prolong the life span of Dalton's Lymphoma Ascites (DLA) and Ehrlich Ascites Carcinoma (EAC) bearing mice and reduced the volume of transplanted solid tumours. The extract inhibited aniline hydroxylase, a P-450 enzyme. The concentration required for 50% inhibition (IC(50)) was found to be 540 microg/ml. The extract was found to inhibit DNA topoisomerase II of Saccharomyces cerevisiae mutant cell cultures and inhibited cell cycle regulatory enzyme cdc25 tyrosine phosphatase (IC(50-25) microg/ml). Antitumour and anticancer activity of P. amarus may be related with the inhibition of metabolic activation of carcinogen as well as the inhibition of cell cycle regulators and DNA repair.
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PMID:Antitumour and anticarcinogenic activity of Phyllanthus amarus extract. 1202 Sep 23

New anticancer drugs targeting DNA topoisomerase I (topo I) are showing activity against human sarcomas. Laboratory studies have indicated that cells responsive to topo I-targeted drugs have elevated levels of topo I, require active DNA replication, and may require a functional apoptotic pathway. In this study, we evaluated these potential markers of topo I-targeted drug sensitivity in 55 cases of human sarcoma (42 high grade, 4 intermediate grade, and 9 low grade). By immunohistochemical staining, we observed elevated topo I expression in 20 of 55 neoplasms (36%). Immunohistochemical staining for the proliferation marker DNA topoisomerase II-alpha (topo II-alpha), showed that 15 of 55 neoplasms (27%) had topo II-alpha indices >50, indicating a large number of actively cycling tumor cells. Abnormal p53 expression was observed in 19 of the 55 cases (35%). None of the cases were interpreted as positive for ALK-1. To complement our immunohistochemical staining of topo I, we isolated functionally active topo I from extracts of a human sarcoma. These isolates demonstrated that sarcoma topo I is sensitive to topo I-targeted anticancer drugs. Of the 55 cases of human sarcoma, 7 (13%) had high levels of topo I, a large number of cycling tumor cells, and normal p53 expression. These are the molecular parameters that might suggest responsiveness to drugs targeting topo I.
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PMID:Human DNA topoisomerase I: An anticancer drug target present in human sarcomas. 1215 58

Sarcomas are known to develop resistance to current chemotherapeutic strategies, displaying a multidrug-resistant phenotype. Mechanisms involved in drug resistance include reduced cellular drug accumulation, drug detoxification as well as alterations in drug target specificity. In seven sarcomas of the pulmonary artery (SPA) and ten leiomyosarcomas of other origin, we studied the immunohistochemical expression of P-glycoprotein (P-gp), multidrug-resistance protein (MRP), lung resistance protein (LRP), metallothionein (MT) and topoisomerase IIalpha. Upregulation was found in tumour cells for P-gp but not for MRP in SPA and other leiomyosarcomas. Topoisomerase IIalpha was expressed at high levels in tissue of primary tumours as well as recurrent tumours. Both P-gp and topoisomerase IIalpha were present in numerous tumour-associated vessels. LRP was expressed at high levels in SPA but to a lesser extent in the other leiomyosarcomas. MT was expressed at low levels but was markedly present at the border of necrosis. The overall survival and the relapse-free survival did not correlate with the expression of these factors. There was no significant relationship between treated and non-treated patients with respect to the expression of the examined molecules. P-gp, but not MRP, may play a role in the development of drug resistance. P-gp, LRP and topoisomerase IIalpha contribute to drug resistance through expression in tumour-associated vessels. Unique high levels of topisomerase IIalpha reflect the high proliferation rate of these tumours. MT seems to serve as a detoxifying agent of metabolites at the border of necrosis. Our findings underline the fact that multiple factors contribute to chemoresistance and that examination of a spectrum of relevant molecules is probably necessary to plan the best therapy.
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PMID:Expression of drug resistance related proteins in sarcomas of the pulmonary artery and poorly differentiated leiomyosarcomas of other origin. 1274 15

Breast irradiation, adjuvant chemotherapy, and tamoxifen are associated with an increased risk of second cancers that may manifest decades after treatment. Although very small, it is nonetheless important for clinicians and women to be aware of and to recognize the risk. Postmastectomy irradiation is associated with a slight increase in the risk of developing a sarcoma or lung cancer after a latency period of more than 10 years. However, the majority of information on radiation-associated cancers is derived from large tumor registries, which reflect outdated radiation treatment practices. Modern treatment approaches, which use lower fraction size (or dose) and limit the exposure of surrounding normal tissue to radiation, are less likely to cause radiation-associated cancers. Adjuvant chemotherapy is not associated with any detectable increased risk of solid tumors beyond that which occurs as the population ages. However, alkylating agents, such as cyclophosphamide, and the topoisomerase II inhibitors, doxorubicin and epirubicin, are associated with two types of cytogenetically distinct leukemias after adjuvant chemotherapy. The absolute risk of developing leukemia is lower by orders of magnitude than the improvement in breast cancer mortality that results from adjuvant chemotherapy. Tamoxifen is associated with a two- to threefold increase in the risk of developing endometrial cancer, or about 80 excess cases per 10,000 treated women at 10 years. The benefits of adjuvant therapy outweigh the risks of developing second cancers. Additional studies are needed to more precisely identify patients who are or are not likely to benefit from adjuvant therapy, and individual host and treatment factors that influence the development of second cancer.
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PMID:Second cancers after breast cancer treatment. 1466 75

As part of a series of studies to discover new topoisomerase II inhibitors, novel pyrimidoacridones, pyrimidophenoxadines, and pyrimidocarbazoles were synthesized, and in vitro and in vivo antitumor activities and DNA-protein and/or DNA-topoisomerase II cross-linking activity as an indicator of topoisomerase II-DNA cleavable complex formation were evaluated. The pyrimidocarbazoles possessed high in vitro and in vivo potencies. Compound 26 (ER-37326), 8-acetyl-2-[2-(dimethylamino)ethyl]-1H-pyrimido[5,6,1-jk]carbazole-1,3(2H)-dione, showed in vitro growth inhibitory activity with respective IC(50) values of 0.049 microM and 0.35 microM against mouse leukemia P388 and human oral cancer KB. In vivo, this compound inhibited the tumor growth of mouse sarcoma M5076 implanted into mice with T/C values of 42% and 13% at 3.13 and 6.25 mg/kg/d respectively without significantly affecting the body weight. In addition, compound 26 (ER-37326) increased the formation of DNA-topoisomerase II cross-linking in P388 cells.
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PMID:Synthesis and evaluation of novel pyrimido-acridone, -phenoxadine, and -carbazole as topoisomerase II inhibitors. 1534 Jan 92


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