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

Two different classes of therapy-related acute myeloid leukemia (t-AML) seem to emerge. One class follows therapy with alkylating agents, increases in frequency with age, often presents with myelodysplasia (MDS), responds poorly to chemotherapy, and shows monosomy 7(-7), monosomy 5(-5), or loss of various parts of the long arms of these chromosomes (5q- and 7q-). The other class is related to therapy with cytostatic drugs targeting at DNA-topoisomerase II, often presents with overt leukemia, responds more favorably to chemotherapy, and shows balanced chromosome aberrations, primarily translocations involving chromosome bands 11q23 and 21q22. These two classes of t-AML may have their counterparts in de-novo acute myeloid leukemia (de-novo AML).
Cancer Genet Cytogenet 1991 Aug
PMID:Two different classes of therapy-related and de-novo acute myeloid leukemia? 165 39

The effect of combinations of the anthracyclines aclarubicin and daunorubicin was investigated in a clonogenic assay using the human small cell lung cancer cell line OC-NYH and a multidrug-resistant (MDR) murine subline of Ehrlich ascites tumor (EHR2/DNR+). It was found that the cytotoxicity of daunorubicin in OC-NYH cells was antagonized by simultaneous exposure to nontoxic concentrations of aclarubicin. Coordinately, aclarubicin inhibited the formation of daunorubicin-induced protein-concealed DNA single-strand breaks and DNA-protein cross-links in OC-NYH cells when assayed by the alkaline elution technique. Aclarubicin had no influence on the accumulation of daunorubicin in these cells. In contrast, the accumulation of daunorubicin in EHR2/DNR+ cells was enhanced by more than 300% when the cells were simultaneously incubated with the MDR modulator verapamil, aclarubicin, or the two agents combined. Yet the cytotoxicity of daunorubicin was potentiated significantly only by verapamil. The increased cytotoxicity of daunorubicin in the presence of verapamil was completely antagonized when aclarubicin was used together with the MDR modulator. Finally, the effect of daunorubicin on the DNA cleavage activity of purified topoisomerase II in the presence and absence of aclarubicin was examined. It was found that daunorubicin stimulated DNA cleavage by topoisomerase II at specific DNA sites. The addition of aclarubicin completely inhibited the daunorubicin-induced stimulation of DNA cleavage. Taken together, these data indicate that aclarubicin-mediated inhibition of daunorubicin-induced cytotoxicity is due mainly to a drug interaction with the nuclear enzyme topoisomerase II. This antagonism at the nuclear level explains why aclarubicin is a poor modulator of daunorubicin resistance even though aclarubicin is able to increase the intracellular accumulation of daunorubicin in a MDR cell line.
Cancer Res 1991 Oct 01
PMID:Antagonistic effect of aclarubicin on daunorubicin-induced cytotoxicity in human small cell lung cancer cells: relationship to DNA integrity and topoisomerase II. 165 44

Topotecan (SK&F 104864), a water-soluble analogue of the topoisomerase I inhibitor camptothecin, is currently in Phase II clinical trial for solid tumors. We have characterized topotecan in terms of its effect upon gamma-radiation-induced cell killing. In colony formation experiments, subtoxic concentrations of topotecan (2 microM) potentiated radiation-induced killing of exponentially growing Chinese hamster ovary or P388 murine leukemia cultured cells. Survival curve shoulders were reduced; the slopes of the exponential portions of the curves were decreased to a small extent. D37 and D10 (radiation dose resulting in 37 and 10% survival of colony-forming ability) values were reduced by approximately 60 and 50%, respectively, in the case of Chinese hamster ovary cells. In P388 cells, topotecan reduced D37 by 35 to 40% and D10 by 20 to 25%. Potentiation of radiation-induced cell killing by topotecan was absolutely dependent upon the presence of the topoisomerase I inhibitor during the first few (less than 30) min after irradiation. Association of topoisomerase I with this effect was confirmed in studies of Chinese hamster ovary cells previously made resistant to camptothecin (and cross-resistant to topotecan), resulting in decreased cellular content of topoisomerase I. These cells were found to be 2- to 3-fold hypersensitive to gamma-radiation-induced killing. P388 camptothecin-resistant cells were further sensitized to the lethal effects of ionizing radiation by nontoxic treatment with the topoisomerase II inhibitor novobiocin, consistent with increased dependence of topoisomerase I-deficient cells upon topoisomerase II.
Cancer Res 1991 Nov 01
PMID:Synergistic cell killing by ionizing radiation and topoisomerase I inhibitor topotecan (SK&F 104864). 165 71

Cells exhibiting decreased topoisomerase II (Topo II) activity are resistant to several drugs that require Topo II as an intermediate. These drugs are cytotoxic due to the formation of a cleavable complex between the drug, Topo II and DNA. Fostriecin belongs to a new class of drugs that inhibit Topo II without inducing the formation of this cleavable complex. We tested fostriecin in three human small-cell lung carcinoma cell lines. GLC4 is the parent line. GLC4/ADR is the P-glycoprotein-negative multidrug-resistant subline, which is resistant to several Topo II inhibitors due to its decreased Topo II activity. GLC4/cDDP is the cisplatin-resistant subline, which displays increased Topo II activity. Topo II activity proved to be 100% in GLC4, 35% in GLC4/ADR and 130% in GLC4/cDDP. The fostriecin concentration causing inhibition of the growth of 50% of the cells (IC50) in the microculture tetrazolium assay following continuous incubation was 11.2, 4.1 and 14.9 microM, respectively. After 1-h incubations, the IC50 was 117.8, 101.3 and 219.8 microM, respectively. Our results indicate a relationship between Topo II activity and fostriecin sensitivity in these closely related cell lines. At least in vitro, fostriecin displayed the capacity to kill cells showing resistance to drugs due to decreased Topo II activity. There was no relationship between this capacity and an increase in the activity of the reduced-folate carrier system, the proposed mechanism for cellular entry of fostriecin, since we found no correlation between the cytotoxicity of fostriecin and that of methotrexate.
Cancer Chemother Pharmacol 1991
PMID:Lack of cross-resistance to fostriecin in a human small-cell lung carcinoma cell line showing topoisomerase II-related drug resistance. 165 25

A new multiple drug-resistant Chinese hamster ovary cell line, CHO-SMR5, has been isolated which demonstrates a direct correlation between reduced cellular topoisomerase II activity (5-fold reduction) and a low level of resistance (3- to 7-fold) to topoisomerase II inhibitors. This cell line, initially selected for resistance to 9-(4,6-O-ethylidene-beta-D-glucopyranosyl)-4'-demethylepipodophylloto xin, exhibits cross-resistance to other topoisomerase II inhibitors including 4'-(9-acridinylamino)methanesulfon-m-anisidide, doxorubicin, and mitoxantrone. The resistant cells show a 4.5-fold decrease in topoisomerase II by immunoblotting when compared to wild-type cells. Drug uptake studies reveal equivalent equilibrium intracellular concentrations of [3H]9-(4,6-O-ethylidene-beta-D-glucopyranosyl)-4'-demethyepipodophyll otoxin in the resistant and parental cells. The catalytic activity of topoisomerase II (decatenation of kinetoplast DNA) is 5-fold less in the drug-resistant cell line relative to wild-type Chinese hamster ovary cells. Drug-induced DNA damage, measured as either formation of DNA double-strand breaks or covalent DNA-enzyme complexes, is 4-fold less in the resistant cell line. Finally, Northern blot analysis demonstrates a 5-fold reduction in topoisomerase II mRNA isolated from log phase CHO-SMR5 cells. These findings suggest that a reduced level of topoisomerase II is likely to be the sole mechanism of drug resistance in this novel cell line.
Cancer Res 1991 Dec 15
PMID:Attenuated topoisomerase II content directly correlates with a low level of drug resistance in a Chinese hamster ovary cell line. 166 Mar 41

Patients with metastatic testis tumors are generally curable using chemotherapy, whereas those with disseminated bladder carcinomas are not. We have compared levels of the nuclear enzyme topoisomerase II in three testis (SuSa, 833K, and GH) and three bladder (RT4, RT112, and HT1376) cancer cell lines which differ in their sensitivity to chemotherapeutic agents. The testis cell lines were more sensitive than the bladder lines to three drugs whose cytotoxicity is mediated in part by inhibiting topoisomerase II: amsacrine; Adriamycin; and etoposide (VP16). The frequency of DNA strand breaks induced by amsacrine was higher (1.5- to 13-fold) in the testis cells than in the bladder cells. The level of topoisomerase II-mediated DNA strand breakage in vitro, measured by filter trapping of amsacrine-induced protein:DNA cross-links, was similarly higher in nuclear extracts from the testis than the bladder cells. Western blot analysis showed a generally higher level of topoisomerase II protein in testis than in bladder cell nuclear extracts. Topoisomerase II protein expression broadly correlated with drug-induced strand breakage in both protein extracts and whole cells, but not with population doubling time. However, despite a 2- to 20-fold increased sensitivity to the different topoisomerase II inhibitors, the testis line 833K had a less than 2-fold higher level of topoisomerase II protein than that of the bladder line RT4. These results indicate that the level of expression of topoisomerase II is an important determinant of the relative chemosensitivity of testis and bladder tumor cell lines, but that additional factors must contribute to the extreme chemosensitivity of testis cells.
Cancer Res 1991 Dec 15
PMID:Relationship between topoisomerase II level and chemosensitivity in human tumor cell lines. 166 Mar 43

Phorbol-12-myristate 13-acetate (PMA), a stimulator of protein kinase C, dramatically decreased topoisomerase II-reactive drug-induced DNA cleavage in HL-60 human leukemia cells. The effect of staurosporine, an inhibitor of protein kinase C, on drug-induced, topoisomerase II-mediated DNA cleavage was quantified in the same cells. Staurosporine decreased the magnitude of 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA)- and etoposide-induced DNA cleavage in a dose- and time-dependent fashion. Measurement of several parameters of cell proliferation revealed no clear and uniform correlation between staurosporine's inhibition of these parameters and its effects on drug-induced DNA cleavage. A direct comparison with PMA's effects on drug-induced DNA cleavage showed that whereas PMA's inhibition of etoposide-induced cleavage was much greater than its inhibition of m-AMSA-induced cleavage, the magnitude of staurosporine's effect on the cleavage produced by the two topoisomerase II-reactive drugs was similar. Thus, although PMA stimulates protein kinase C and staurosporine inhibits this enzyme, it is unlikely that the actions of either on topoisomerase II-reactive, drug-induced DNA cleavage are mediated directly via protein kinase C. Furthermore, it is likely that the mechanisms by which PMA and staurosporine inhibit topoisomerase II-reactive drug-induced cleavage are different.
Cancer Chemother Pharmacol 1991
PMID:The effect of staurosporine on drug-induced, topoisomerase II-mediated DNA cleavage in human leukemia cells. 166 Mar 53

Surgical specimens from 15 medulloblastoma patients were used to establish early passage cultures. In vitro sensitivity to a battery of cytotoxic agents, including some in current medulloblastoma treatment protocols, was measured. Drug sensitivity was assessed at clinically relevant drug concentrations using the 3H-thymidine uptake method. Tumours were predicted to be sensitive if greater than 37% were killed by exposure to drugs at clinically achievable levels. A poor response to vincristine (Vcr), cis-platin (CDDP), hydroxyurea (HU) or diaziquone (AZQ) (no responders), and cytosine arabinoside (AraC) (1/12), was seen. Nine of ten tumours tested were sensitive to mafosfamide (Mfs); seven out of 12 were sensitive to carmustine (BCNU), 12 of 13 to teniposide (VM-26) and seven of 13 to etoposide (VP16-213). VM-26 was the best of the agents tested with most tumours responding to very low concentrations of drug, suggesting that the role of epipodophyllotoxins in treatment of brain tumours be further investigated. Despite the marked sensitivity of the medulloblastomas to the epipodophyllotoxins, three early passage cultures were much more resistant to these drugs than the average for the group. The basis of this resistance was investigated. Deficient cellular uptake of drug was excluded as a cause of resistance. One resistant early passage culture displayed low cellular activity of topoisomerase II and decreased levels of drug induced enzyme-DNA strand break activity. This was not the case for the other resistant early passage cultures: the basis of resistance in these cells does not appear to be due to any previously reported mechanism.
Br J Cancer 1991 Dec
PMID:Comparison of in vitro activity of epipodophyllotoxins with other chemotherapeutic agents in human medulloblastomas. 166 32

CI-921 (NSC 343499; 9-[[2-methoxy-4-[(methylsulphonyl)amino]phenyl]amino] -N,5-dimethyl- 4-acridinecarboxamide) is a topoisomerase II poison with high experimental antitumour activity. It was administered by 15 min infusion to 16 evaluable patients with non-small cell lung cancer (NSCLC) (7 with no prior treatment, 9 patients in relapse following surgery/radiotherapy) at a dose (648 mg/m2 divided over 3 days, repeated every 3 weeks) determined by phase I trial. Patients had a median performance status of 1 (WHO), and median age of 61 years. The histology comprised squamous carcinoma (11), adenocarcinoma (1), mixed histology (2), bronchio-alveolar carcinoma (1) and large cell undifferentiated carcinoma (1). Neutropenia grade greater than or equal to 3 was seen in 15 patients, infections with recovery in 3, and grand mal seizures in 1 patient. Grade less than or equal to 2 nausea and vomiting occurred in 66% courses and phlebitis in the infusion arm in 37%. 1 patient with squamous cell carcinoma achieved a partial response lasting 5 months. Further testing in this and other tumour types using multiple daily schedules is warranted.
Eur J Cancer 1991
PMID:Phase II study of the amsacrine analogue CI-921 (NSC 343499) in non-small cell lung cancer. 166 18

The cellular levels of topoisomerase II expression were compared between 10 fresh human tumors and normal tissues to predict the selective anticancer effect of its inhibitors such as adriamycin and VP-16. Topoisomerase II expression was observed in 9 of the 10 tumor tissues (90.0 per cent), 3 of which showed extremely high levels, whereas only 5 of the normal tissues (50.0 per cent) expressed any cellular topoisomerase II and the levels were not higher than those seen in the cancer cells. Six of the 9 positive tumors showed a higher level of topoisomerase II expression than the normal tissues, while the other 3 showed the same level. It can be interpreted from these results that topoisomerase II inhibitors could be effective in cancer patients due to the greater level of this enzyme in tumor cells than in normal tissues. Thus, it is suggested that a comparative analysis of topoisomerase II expression between tumors and normal tissues may be useful for predicting the selective cytotoxicity of topoisomerase II inhibitors in clinical practice.
 ...
PMID:mRNA expression of topoisomerase II in human tumors and normal tissues. 166 37


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