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)

CPT-11 is a derivative of camptothecin, a topoisomerase-I inhibitor with marked cytotoxic activity. We examined the cytotoxicity of CPT-11 and its metabolite SN-38 for primary gastrointestinal carcinoma and various recurrent carcinomas which were cultured on contact-sensitive plates (CSPs). The response rate of seven gastrointestinal carcinomas for either CPT-11 or SN-38 was 71% (5/7). The response was higher than those for other anticancer agents, including adriamycin (ADM), cisplatinum (CDDP) and 5-fluorouracil (5-FU). The mean percent survival of these tumor cells was 69% when incubated with 25 ng/ml of SN-38, which was the lowest survival for all the anticancer drugs tested. IN the case of recurrent carcinomas, the response rate to either CPT-11 or SN-38 was 60% (3/5), and was higher than the rates for MMC, CDDP or 5-FU. The mean percent survival of the recurrent carcinoma cells was 76% in the presence of 25 ng/ml SN-38, and this was once again the lowest survival rate. CPT-11 had a stronger inhibitory effect against one carcinoma than SN-38 when a clinical drug concentration was added to the culture medium, suggesting that CPT-11 itself was cytotoxic. IN addition, one carcinoma with a low response to CDDP also showed no response to CPT-11, but was very occurred because of decreased conversion of CPT-11 to SN-38. Our results suggest that CPT-11 may be a useful agent for the treatment of both primary gastrointestinal cancer and various recurrent carcinomas.
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PMID:Cytotoxicity of CPT-11 and SN-38 for gastrointestinal and recurrent carcinomas cultured on contact-sensitive plates. 801 40

The induction of sister-chromatid exchanges (SCE) in cultured human lymphocytes by four inhibitors of DNA topoisomerases: m-amsacrine, camptothecin, etoposide and nalidixic acid has been evaluated. Although the four compounds apparently increase the frequency of SCE, the effect of nalidixic acid is weak because only a statistically significant positive response was found in one donor at the highest concentration (500 microM). The other compounds tested act as SCE inducers in both donors, camptothecin being the most effective. In addition, the influence of these four topoisomerase inhibitors on the SCE frequency induced by MMC was also analysed. The results reveal that less than additive SCE effect was induced by the combined treatments which could suggest that the process leading to SCE induction by MMC and the four inhibitors of DNA topoisomerases are not totally independent.
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PMID:Sister-chromatid exchanges (SCE) induction by inhibitors of DNA topoisomerases in cultured human lymphocytes. 869 26

The topoisomerase II (topo II) inhibitors etoposide (VP-16) and merbarone (MER) were investigated with the in vivo micronucleus test (MN test) combined with fluorescence in situ hybridization (FISH) using the mouse minor satellite DNA probe to discriminate MN of clastogenic and aneugenic origin. All experiments were performed with male (102/ElxC3H/El) F1 mice bred in the mouse colony of the GSF Research Center. The sample size per experimental group was five animals and 2,000 polychromatic erythrocytes (PCE) were scored per animal from coded slides in the conventional MN test. A separate set of coded slides was used for the FISH analysis. All treatments consisted of single intraperitoneal injections. Colchicine (COL, 3 mg/kg) and mitomycin (MMC, 1 mg/kg) were used as a positive control aneugen and clastogen, respectively, and these compounds produced the expected responses. A dose of 1 mg/kg VP-16 induced 3.44% MNPCE (compared to the concurrent solvent control of 0.37%, P < 0.001) and of these 39.9% (1.4% MNPCE) showed one or more fluorescent signals. MER (7.5-60 mg/kg) increased the MNPCE frequencies in a dose-dependent manner, with 15 mg/kg being the lowest positive dose. At the highest dose of 60 mg/kg of MER, a total of 4.26% MNPCE were found (compared to 0.31% in the concurrent solvent control, P < 0.001) and of these 46.2% (2.0% MNPCE) contained one or more fluorescent signals. The data demonstrate that VP-16 and MER induced both clastogenic and aneugenic events despite their different modes of topo II inhibition.
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PMID:Etoposide and merbarone are clastogenic and aneugenic in the mouse bone marrow micronucleus test complemented by fluorescence in situ hybridization with the mouse minor satellite DNA probe. 1260 78

Fanconi anemia (FA) patients exhibit bone marrow failure, developmental defects and cancer. The FA pathway maintains chromosomal stability in concert with replication fork maintenance and DNA double strand break (DSB) repair pathways including RAD51-mediated homologous recombination (HR). RAD51 is a recombinase that maintains replication forks and repairs DSBs, but also rearranges chromosomes. Two RecQ helicases, RECQL5 and Bloom syndrome mutated (BLM) suppress HR through nonredundant mechanisms. Here we test the impact deletion of RECQL5 and BLM has on mouse embryonic stem (ES) cells deleted for FANCB, a member of the FA core complex. We show that RECQL5, but not BLM, conferred resistance to mitomycin C (MMC, an interstrand crosslinker) and camptothecin (CPT, a type 1 topoisomerase inhibitor) in FANCB-defective cells. RECQL5 suppressed, while BLM caused, breaks and radials in FANCB-deleted cells exposed to CPT or MMC, respectively. RECQL5 protected the nascent replication strand from MRE11-mediated degradation and restarted stressed replication forks in a manner additive to FANCB. By contrast BLM restarted, but did not protect, replication forks in a manner epistatic to FANCB. RECQL5 also lowered RAD51 levels in FANCB-deleted cells at stressed replication sites implicating a rearrangement avoidance mechanism. Thus, RECQL5 and BLM impact FANCB-defective cells differently in response to replication stress with relevance to chemotherapeutic regimes.
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PMID:RECQL5 and BLM exhibit divergent functions in cells defective for the Fanconi anemia pathway. 2552 Jan 94