Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CPT-11 and Topotecan are a new semisynthetic derivative of CPT, and have been shown to inhibit DNA topoisomerase I and to have a strong antitumor activity with low toxicity against murine tumor. On the other hard, the new antitumor compounds, NC-190 and IST-622 have been shown to inhibit DNA topoisomerase II, and the clinical study are currently under progress. A phase II study of CPT-11 demonstrated that CPT-11 was a very active agent which a acceptable toxicities against patient with advanced non-small cell lung cancer and small cell lung cancer.
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PMID:[DNA topoisomerase inhibitor]. 133 23

Woodfruticosin (woodfordin C) (WFC), a new inhibitor of DNA topoisomerase II (topo-II), was isolated from methanol extract of Woodfordia fruticosa Kurz (Lythraceae) and studied for in vitro and in vivo antitumor activities in comparison with Adriamycin (ADR) and etoposide (ETP), well known inhibitors of topo-II. The inhibitory activity against DNA topo-II shown by WFC was much stronger than that shown by ETP or ADR. WFC inhibited strongly intracellular DNA synthesis but not RNA and protein synthesis. On the other hand, WFC had a weaker growth inhibitory activity against various human tumor cells than ETP or ADR, but it showed remarkable activity against PC-1 cells and moderate activity against MKN45 and KB cells. Furthermore, WFC had in vivo growth inhibitory activity against s.c. inoculated colon38. These results indicate that the mechanism by which WFC exhibits antitumor activity may be through inhibition of topo-II.
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PMID:Woodfruticosin (woodfordin C), a new inhibitor of DNA topoisomerase II. Experimental antitumor activity. 133 1

The cellular content and the cell-cycle distribution of the 170 kD- and 180 kD-isoforms of DNA topoisomerase II were investigated in human tumor cells with specific monoclonal antibodies and by immunofluorescent detection with flow cytometry. Levels of topo II alpha were almost three-fold higher than the beta-isozyme in exponentially growing cells in vitro. In contrast, topo II alpha but not beta, was markedly reduced in plateau-phase cells. Tumor cells from surgical biopsies, mainly in G0/G1 phase, exhibited a 95% beta- versus 5% alpha-isoform expression. These results support the hypothesis that topo II alpha is mainly related to DNA synthesis, and topo II beta to DNA transcription.
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PMID:Topoisomerase II alpha and beta in human tumor cells grown in vitro and in vivo. 133 75

Recombinant TNF as a single agent for human cancer appears to be of limited value. However, rTNF has synergistic anticancer effects when combined with chemotherapeutic drugs targeted at DNA topoisomerase II. This effect of rTNF has been observed in several in vitro and in vivo tumor models, both in animal and human studies. The mechanism of this interaction appears to involve lesions to the DNA of tumor cells mediated by inhibition of DNA topoisomerase II. The combinations of rTNF plus doxorubicin and rTNF plus etoposide administered systemically are currently under evaluation by clinical trials in patients with advanced cancers. Determination of the efficacy of such combination therapy must await the completion of phase I and II trails. Other routes of administration that might increase the local concentration of rTNF and could be combined with topoisomerase II-targeted drugs include intravesical administration and the use of tumor-infiltrating lymphocytes.
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PMID:Tumor necrosis factor and chemotherapeutic drugs targeted at DNA topoisomerase II for the treatment of genitourinary malignancies. 134 88

The expression of the drug resistance markers P glycoprotein (P-170), glutathione S transferase-pi (GST-pi) and DNA topoisomerase II (Topo II) was analyzed in 16 human kidney carcinoma cell lines, 18 hematological malignancies, and 14 human breast carcinomas. We found a tendency for coexpression of increased P-170 and GST-pi and of increased P-170 and decreased Topo II expression in kidney carcinoma cell lines. A similar tendency was found between P-170 and GST-pi expression in breast carcinomas. In contrast, hematological malignancies did not show such a coexpression of resistance markers. Furthermore, we found interrelationships between the expression of resistance markers, resistance to doxorubicin or vincristine, and doubling times of kidney carcinoma cell lines. This indicates that the proliferative activity of tumor cells plays a role for the expression of resistance markers and the development of resistance to cytostatic drugs.
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PMID:Immunohistochemical detection of P glycoprotein, glutathione S transferase and DNA topoisomerase II in human tumors. 135 60

Reduced drug accumulation is the most common functional change accompanying development of P-glycoprotein-associated multidrug resistance. One of our laboratories showed earlier that the anthracycline analogue 4'-deoxy-4'-iododoxorubicin (DIDOX) was accumulated to identical levels in Ehrlich ascites tumor (EHR2) and daunorubicin (DNR)-resistant EHR2/DNR+ cells (E. Friche, P. B. Jensen, T. Skovsgaard, and N. I. Nissen, J. Cell. Pharmacol., 1:57-65, 1990). In this communication, we show that weekly treatment of EHR2-bearing mice with 4, 8, or 12 mg of DIDOX/kg/week led to the development of three DIDOX-resistant cell lines, EHR2/DIDOX-1, EHR2/DIDOX-2, and EHR2/DIDOX-3. The levels of DIDOX accumulation and retention and its outward transport were similar in the drug-sensitive and three drug-resistant cell lines. By contrast, the accumulation of the active DIDOX metabolite, 13-dihydro-DIDOX (13-OH-DIDOX), the parent compound doxorubicin, and daunorubicin were all decreased in proportion to the resistance of the cells. In EHR2/DIDOX-3 cells, the reduction in daunorubicin accumulation coincided with the development of P-glycoprotein as demonstrated by Western blot and flow cytometry with C219 antibody. DIDOX had no effect on the photolabeling of P-glycoprotein by [3H]azidopine, whereas 13-OH-DIDOX inhibited this labeling in a concentration-dependent manner. Subsequent analysis of topoisomerase II activities and amounts in EHR2/DIDOX-3 cells revealed decreased DNA topoisomerase II catalytic activity. The amounts of immunoreactive DNA topoisomerase II from EHR2/DIDOX-1, EHR2/DIDOX-2, and EHR2/DIDOX-3 cells were about 89%, 73%, and 52%, respectively, of that seen in the drug-sensitive cells. We also found that teniposide stabilized DNA-protein complexes in EHR2/DIDOX-3 but they never reached the level seen in EHR2 cells. Because it has been reported that DIDOX is rapidly metabolized to 13-OH-DIDOX, we postulate that the development of resistance to DIDOX in vivo is due in part to its metabolite, 13-OH-DIDOX, which is a substrate for plasma membrane glycoprotein, and in part to DIDOX, which is an inhibitor of topoisomerase II.
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PMID:Characterization of tumor cell resistance to 4'-deoxy-4'-iododoxorubicin developed in Ehrlich ascites cells in vivo. 135 19

Significant prolongation of survival time among the patients with advanced ovarian cancer has been brought under the development of surgery and chemotherapy, but even those with clinical remission shows sometimes recurrence. For the recurrent ovarian cancer patients at present there are no definite strategy to treat the recurrent cases. Under these circumstance, we have reviewed the current treatment of cytoreductive surgery and chemotherapy for the recurrent cases. 1) surgical treatment Generally, in the cases of recurrent ovarian cancer, cytoreductive surgery is required to minimize the residual tumour in the abdomen. But sometimes we can find the distant metastasis including liver, lung, and lymph node. This means that surgery is not sufficient for control of recurrent tumor. Further adjuvant chemotherapy will be required to control metastatic tumors. 2) chemotherapy After the detail assessment of the initial treatment of cases, at first we should think about retreatment with CDDP-based regimen and secondly about dose-intensification of CDDP or CBDCA for the CDDP-resistant cases. And as combination regimens, topoisomerase inhibitors, etoposide or CPT-11 are also preferable to use, alkylating agents such as ifosfamide, 5-fluorouracil, and some current trials with new drug, taxol are effective for recurrent cases. In conclusion, further active chemotherapy using platinum compounds, topoisomerase inhibitors, taxol will be achieved for the control of the recurrent cases of ovarian cancer.
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PMID:[Treatment of recurrent ovarian cancer]. 135 32

A survey is presented of two types of resistance to drugs acting on cellular topoisomerase enzymes, that occurring by altered drug transport and that occurring by altered target interaction. Particular attention is paid to the use of pairs of diagnostic drugs, one susceptible and one refractory to a particular resistance mechanism, in the determination of such resistance in cultured cells. Two pairs of drugs, each including the antitumor agent amsacrine, are used in the analysis of a number of cell lines. Also it is suggested that some normal hemopoietic precursor cells may exhibit two types of multidrug resistance, and that this should be taken into account in determining selectivity of topoisomerase-directed drugs for tumor cells.
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PMID:Resistance mechanisms to topoisomerase poisons: the application of cell culture methods. 136 Feb 75

Squamous cell carcinoma of the upper aerodigestive tract presents significant problems in determining appropriate treatment regimens. Staging aided by sophisticated investigations allows for planning of treatment, but there is a definite need for a specific and reproducible marker to quantify biological aggressiveness. For some classes of tumors the DNA ploidy of cells, as determined by flow cytometry, has shown good correlation to pathologic grading and prognosis. Using a mathematical model, it is possible to calculate the S-phase fraction, which is indicative of proliferative activity and may reflect tumor aggressiveness. However, this parameter is often difficult to determine reliably in squamous cell carcinoma. An optimal marker would be a measureable protein related to proliferation. An attempt was made to use flow cytometry to measure the nuclear enzyme topoisomerase II to assess proliferation in cultured cell lines. Although the antibody was specific to the extracted protein, constituents of the rabbit serum bound non-specifically throughout fixed cells. Further purification of this antibody preparation could realize its diagnostic potential. Antibody against proliferating cell nuclear antigen was more specific, resulting in good correlation flow cytometrically with the S-phase fraction of the cultured cell lines. The results obtained with these protein markers deems further investigation into their use as prognostic indicators. The protocol has been established to apply this technology to tumor samples and establish a meaningful parameter of biological behavior of tumors, upon which treatment regimens can be confidently based.
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PMID:Measurement of proliferative index in squamous cell carcinoma by flow cytometry. 136 86

In an attempt to characterize and overcome tumor cell resistance to amsacrine (m-AMSA), we studied the structure-activity relationships for amsacrine and seven of its analogs. Using the human leukemic cell line, CCRF-CEM, and its derivatives that express either P-glycoprotein (Pgp)-associated multidrug resistance (MDR) (CEM/VLB100) or altered topoisomerase II-associated MDR (at-MDR) (CEM/VM-1), we assessed antitumor effects of these drugs in a 48-hr growth inhibition assay. We also measured drug-topoisomerase II interactions in an intact cell assay that permits quantitation of drug-stabilized DNA-topoisomerase II complexes. We found that among the tested compounds, amsacrine has an intermediate effect on cell growth in all three cell lines. The CEM/VM-1 cells were 8.6-fold cross-resistant to m-AMSA, and the cross-resistance to the analogs was from 3.0- to 10.5-fold. In the CEM/VLB100 cells, the resistance pattern was different: several analogs, including amsacrine, showed little or no cross-resistance (0.5- to 2.8-fold), whereas for those compounds with substituents at position 3 on the acridine ring, resistance was relatively higher (9.9- or 16.2-fold). Substituents at this position substantially decrease the lipophilicity of the two compounds examined, probably because they both contain amino groups that would be charged at physiologic pH. Compound 12489, having a 1'-NHSO2C6H4NH2 substituent, was very potent in the three cell lines, showing only a slightly higher IC50 value in the CEM/VM-1 line and a lower IC50 value in the CEM/VLB100 and in the CEM cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Structure-activity studies of amsacrine analogs in drug resistant human leukemia cell lines expressing either altered DNA topoisomerase II or P-glycoprotein. 136 24


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