Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.3 (topoisomerase)
 9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was designed to investigate the biologic and molecular basis of the aggressive behavior of high-grade post-thymic T-cell malignancies. Freshly frozen tumor tissues from (1) human T-cell leukemia/lymphoma virus type I (HTLV-I)-positive adult T-cell lymphoma (ATL) (7 cases), (2) HTLV-I-negative aggressive T-cell lymphoma (12 cases), and (3) HTLV-I-negative nonaggressive T-cell lymphoma (11 cases) were studied for the expression of several growth-related genes or proliferation antigens including interleukin-2 receptor (IL-2R), Ki-67, transforming growth factor-beta (TGF-beta), topoisomerase, and the multidrug resistance (MDR) gene by immunohistochemistry and Northern blot hybridization. Our results showed that tumor cells associated with HTLV-I and anaplastic morphology had an enhanced expression of Ki-67, TGF-beta, and topoisomerase, as compared to nonaggressive T-cell lymphoma. The expression of IL-2R was limited to ATL and one Ki-1 lymphoma. The MDR gene was frequently expressed in ATL, but only infrequently in other, HTLV-I-negative, malignancies. Clinical progression or relapse was associated with the expression of MDR, in addition to an increased expression of Ki-67. We therefore conclude that the aggressive clinical behavior of high-grade T-cell lymphoma may result mainly from the high proliferative activity of tumor cells, but the association with HTLV-I and clinical relapse is further complicated by the development of drug resistance.
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PMID:Expression of growth-related genes and drug-resistance genes in HTLV-I-positive and HTLV-I-negative post-thymic T-cell malignancies. 167 81

DNA topoisomerase II (topo II) is the target of several clinically useful anticancer drugs. Several of these agents, such as doxorubicin and etoposide (VP-16), are used to treat non-Hodgkin's lymphomas (NHL). To understand the therapeutic selectivity of these drugs, a series of 33 cases of NHL for topo II were analyzed using an immunohistochemical technique that detects the enzyme in formalin-fixed, paraffin-embedded tissue. The average topo II index of high grade (Working Formulation) NHL was 48.6 with a range from 24.4 to 79.7. The average topo II index of low grade (Working Formulation) NHL was 4.4 with a range from 0.9 to 11.2. These two values are statistically different (P < .01). The intermediate grade (Working Formulation) NHL are a heterogeneous group based on topo II staining. The average topo II index value for the intermediate grade neoplasms was 26.7 with a range from 1.4 to 54.9. Because the proliferation marker Ki-67 has been shown to be of prognostic importance when used in the analysis of NHL, 27 cases for also were analyzed for MIB1 (Ki-67). The average MIB1 index of the high grade NHL was 59.8 with a range from 40.7 to 80.3. This average is statistically different (P < .01) than the average MIB1 index of 11.2 (range 1.7-28.3) found in the low grade NHL. Similar to results with topo II, the intermediate grade NHL was a heterogeneous group of tumors with respect to MIBI staining and had an average MIB1 index of 49.1 with a range from 8.9 to 86.7. These results show that high grade NHL have topo II and MIB1 indices that are significantly higher than low grade NHL. Intermediate NHL are more heterogeneous and have topo II and MIB1 indices that range from low to high.
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PMID:Immunohistochemical staining for DNA topoisomerase II in non-Hodgkin's lymphomas. 761 Nov 82

Suramin cytotoxicity was studied in a panel of human lung cancer cell lines by the MTT assay. The concentrations of suramin which induced 50% growth inhibition (IC50) ranged from 130 to 3715 microM for the cell lines growing in medium containing 10% fetal calf serum (FCS). In only one cell line was the IC50 at a concentration that can be reached in plasma of patients treated with suramin. Suramin was 18 and 3.3 times more cytotoxic on NCI-N417 cells growing in 2% FCS and in HITES serum-free medium, respectively, than growing in 10% FCS. No difference in suramin cytotoxicity was observed between small and non-small cell lung cancer cell lines. At the lower concentrations tested, suramin stimulated proliferation of the two small cell lung cancer cell lines, NCI-H187 and NCI-N417. Of several growth factors tested, none induced stimulation of growth in NCI-H187 and NCI-N417 cell lines, nor did they in any way alter the stimulatory effect of suramin. Cell counting, DNA flow cytometric analysis and Ki-67 staining confirmed a higher proliferative state in suramin-exposed NCI-H187 cells as compared with untreated cells. However, topoisomerase II-alpha gene expression remained unchanged, as assessed by northern blot analysis and immunostaining. Suramin had an inhibitory effect on topoisomerase II activity, as assessed by the kDNA decatenation assay, with an IC50 of approximately 40 microM. In conclusion, suramin has significant cytotoxic activity in a minority of human lung cancer cell lines, and it stimulates proliferation in some instances. The pleiotropic action of suramin observed should caution on the possibility of tumour acceleration in patients being treated with this drug.
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PMID:Effects of suramin on human lung cancer cell lines. 771 32

In this report we analyzed the mRNA expression of the resistance-related enzymes DNA topoisomerase II (Topo II), thymidylate synthase (TS), glutathione S-transferase-pi (GST-pi) and glutathione peroxidase (GP) in childhood acute lymphoblastic leukemia (ALL) and their correlation to the proliferative activity, determined by Ki-67. RNA of blast cells from 54 children with untreated ALL were examined by dot blot hybridization. We found a significant positive correlation between Topo II and TS and cell proliferation. No significant correlation was detected between the mRNA expression of the glutathione-dependent enzymes GST-pi or GP and Ki-67. The results were substantiated by a semiquantitative RT-PCR-assay and by immunocytochemistry.
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PMID:Messenger RNA expression of resistance factors and their correlation to the proliferative activity in childhood acute lymphoblastic leukemia. 788 95

DNA topoisomerase type II (DT-II) is a major component of interphase nuclear matrix fractions, present in S-phase of the cell cycle. A series of 80 carcinomatous breast surgical samples was evaluated by immunohistochemistry, using a polyclonal antibody in a comparison with Ki-67 antiserum. A correlation with clinico-pathological data was also performed. Infiltrating ductal and lobular carcinomas constantly express DT-II with varying intensity of nuclear staining; a similar immunohistochemical pattern is observed with Ki-67. A frequent co-expression of DT-II and Ki-67 is encountered with double immunostaining; accordingly to these data, a linear relationship is evident when linear regression is employed. In addition, significant relationships between DT-II values and tumour size, histological grade and node involvement are shown, while an inverse correlation is appreciable between DT-II and oestrogen receptors and progesterone receptors. DT-II may be considered to be an additional operational marker for the proliferating fraction of cells in breast carcinomas.
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PMID:Immunocytochemical detection of DNA topoisomerase type II in primary breast carcinomas: correlation with clinico-pathological features. 821 34

Most developing lymphocytes spontaneously die in the thymus during positive and negative selection of the T cell repertoire. By evaluating the expression of the proliferation antigens Ki-67 and PCNA, we demonstrated here that more than 95% of thymocytes are potentially proliferating. The coincidence within the same cell population of death and proliferation is thus apparent in developing thymocytes. Using dual-parameter cytometric techniques to evaluate in single cells the amount of DNA versus light-scattering values, we found that spontaneous thymocyte apoptosis occurs with similar frequency in all the cycle phases, whereas apoptosis induced by the anti-topoisomerase-II, etoposide (which is the consequence of irreversible DNA damage), takes place with higher frequency in S and G2 phases (i.e., in those cycle phases in which DNA is subjected to torsional constraints). The capability of thymocytes to enter apoptosis was also monitored by digesting DNA in situ with DNase I (a nuclease that cleaves DNA mimicking the nuclear damage common to most apoptotic suicides). We also show that endonuclease-mediated DNA digestion occurs to a similar extent in cells with different DNA contents, i.e., in cycle phases in which the superstructural organization of chromatin is markedly different.
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PMID:Spontaneous apoptosis of thymocytes is uncoupled with progression through the cell cycle. 898 20

DNA topoisomerase II alpha (topo II alpha) is associated with active cell proliferation and is a target for chemotherapeutic agents administered to patients with ovarian cancer. To evaluate the biologic significance of topo II alpha expression in human ovarian carcinomas, we examined the expression of this protein immunohistochemically in tissue sections from 99 patients with ovarian cancer (85 common epithelial carcinomas, 14 germ cell tumors). We also measured topo II alpha and nuclear DNA content by two-parameter flow cytometry in 29 cases to evaluate possible qualitative changes of topo II alpha in the cell cycle of ovarian cancer cells. We observed a significant correlation of the labeling indices (LIs) of topo II alpha and Ki-67. The topo II alpha-to-Ki-67 ratio in germ cell tumors significantly exceeded that in common epithelial ovarian carcinomas (P = .038). Among the latter, the topo II alpha-to-Ki-67 ratio was significantly higher in serous cystadenocarcinomas than in mucinous cystadenocarcinomas. Two-parameter flow cytometric analysis revealed that topo II alpha expression was mainly observed in cells at the S to G2/M phases of the cell cycle, but, in some cases, topo II alpha positivity was detected in cells at G1. A significantly higher topo II alpha-to-Ki-67 ratio was detected in tumors with topo II alpha-positive cells at the G1 than in tumors in which topo II alpha-positive cells were not at G1. Results indicated that quantitative as well as quantitative changes in topo II alpha occur in human ovarian carcinomas.
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PMID:Immunohistochemical and two-parameter flow cytometric studies of DNA topoisomerase II alpha in human epithelial ovarian carcinoma and germ cell tumor. 950 90

We report 4 unusual cases of myelodysplastic syndrome with distinct persistent nodular lesions noted on serial bone marrow examinations, even during remission. The lesions were predominantly composed of immature monocytes that stained positively for CD68. Trisomy 9 and 11 were demonstrated in the cells of the nodular lesions and surrounding marrow of 1 patient, indicating the same clonal origin. Evaluation of p53 glycoprotein, retinoblastoma protein (pRb), proliferation-related protein (Ki-67), multiple drug-resistant enzyme glutathione-S-transferase pi, and topoisomerase IIalpha (Topo IIalpha) revealed decreased topoisomerase expression within the nodular lesions compared with the surrounding marrow and absence of Ki-67 antigen within nodular lesions. Most cells in the lesion were not in a proliferative cycle, with very low expression of Topo IIalpha, which may explain the apparent drug resistance of these nodular lesions.
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PMID:Nodular lesions of monocytic component in myelodysplastic syndrome. 1019 82

To investigate the effect of ultraviolet (UV) irradiation on the expression of cell cycle-associated proteins, melanocytic nevi from healthy volunteers were partially covered, irradiated with a defined UV dose, and excised 1 week thereafter. The irradiated and the protected parts were examined separately by conventional microscopy and immunohistochemistry using the antibodies Ki-S11 (Ki-67), Ki-S7 (topoisomerase IIalpha), PC10 (proliferating cell nuclear antigen [PCNA]), DO-7 (p53), 6B6 (p21WAF1/Cip1), and the melanocytic marker HMB-45. DNA nick-end labeling was used as a marker of apoptosis. Irradiation resulted in morphological changes and increased HMB-45 reactivity. Proliferation, as assessed by Ki-67 and topoisomerase IIalpha expression, was also clearly enhanced in the UV-exposed areas. This was confirmed by the appearance of occasional mitotic figures. PCNA expression levels markedly exceeded those of the proliferation markers and did not correlate with the latter in most cases. p21 immunolabeling indices were also consistently augmented after UV exposure; hence it is likely that growth-inhibitory mechanisms partly compensate for the proliferative impulse, and the disproportional rise in PCNA expression probably reflects DNA repair activity. Enhanced p53 immunostaining in four cases suggests that the induction of p21 after irradiation may be p53 mediated, whereas no concomitant apoptotic events were observed. We conclude that UV light can stimulate the proliferative activity of melanocytes in melanocytic nevi, but that simultaneously cell cycle inhibitors are activated to permit DNA repair.
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PMID:Enhanced expression of Ki-67, topoisomerase IIalpha, PCNA, p53 and p21WAF1/Cip1 reflecting proliferation and repair activity in UV-irradiated melanocytic nevi. 986 36

Immunohistochemical detection of cell proliferation-associated antigens was investigated in 28 cases of adenoid cystic carcinoma (ACC) and 20 cases of pleomorphic adenoma (PA), using antibodies against DNA topoisomerase type II alpha (topo-II) (Ki-S1) and Ki-67 (MIB-1). The correlation of staining indices with clinicopathological data, histological features and prognosis was also studied. The topo-II value was significantly higher in ACC than in PA (P<0.0001), and highest in the solid growth pattern of ACC. In addition, significant relationships were found between topo-II values and clinical features such as local recurrence, surgical margins, and distant metastases. By log-rank test, the topo-II index was also correlated significantly with patient survival (P<0.01). The values of topo-II index paralleled those of Ki-67 index in ACC, and a correlation coefficient of 0.97 was obtained. Topo-II may be considered an additional marker for estimating the proliferating fraction of cells and for predicting the short-term prognosis for patients with salivary gland tumors.
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PMID:Immunohistochemical detection of DNA topoisomerase type II alpha and Ki-67 in adenoid cystic carcinoma and pleomorphic adenoma of the salivary gland. 1006 42


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