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)

Caffeine (3,7-dihydro-1,3,7,-trimethyl-1H-purine-6,6-dione; CAF) is known to potentiate the cytotoxic effects of DNA damaging agents such as ionizing radiation and alkylating agents. In contrast, however, the cytotoxic and cytostatic activity of aromatic, DNA-intercalating, DNA topoisomerase II inhibitors such as Adriamycin, ellipticine, or mitoxantrone are diminished in the presence of CAF. To resolve whether the protective effect of CAF is associated with a particular mechanism of drug interaction (e.g., intercalation into DNA, inhibition of DNA topoisomerase II), or the aromatic nature of the drug structure, per se, we have presently studied the effects of CAF on the cytostatic and cytotoxic action of camptothecin (CAM) and its less toxic but more water soluble derivative topotecan (TPT) on HL-60 human myelogenous leukemia cells: both drugs have aromatic structures but are nonintercalating inhibitors of DNA topoisomerase I. By using spectroscopy and titration microcalorimetry, we have also studied the direct interaction between CAF and TPT in solution. Low (20 nM) concentrations of CAM or TPT perturbed progression of HL-60 cells through S-phase, whereas higher concentrations (0.15 microM) of these drugs induced apoptosis; both effects were easily demonstrable after 4 h of treatment. When added simultaneously with CAM or TPT, CAF prevented both effects. The protective effect of CAF was concentration dependent and evident within the concentration range of 1-5 mM; nearly total protection was seen at a CAF concentration of 5 mM. The bathochromic and hypochromic shift in the absorption spectrum of the water soluble compound TPT upon addition of CAF indicated that CAF and TPT interact (stack) in a fashion similar to that previously observed for CAF and DNA intercalators. Microcalorimetric measurements of TPT titration with CAF indicate an exothermic reaction between these compounds (the enthalpy change was delta H degree = -4.2 kcal/mol), which is consistent with a stacking model of CAF-TPT interaction. Thus, the ability of CAF to protect HL-60 cells against the cell kinetic effects of CAM or TPT, as in the case of DNA intercalating topoisomerase II inhibitors, is most likely due to formation of complexes between CAF and these aromatic molecules, which result in reducing the effective concentration of the free form of these drugs available to the cells.
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PMID:Caffeine prevents apoptosis and cell cycle effects induced by camptothecin or topotecan in HL-60 cells. 840 36

Irinotecan hydrochloride (CPT-11), topotecan, sobuzoxane, NC-190, and IST-622 are unique topoisomerase inhibitors and are investigational in Japan. CPT-11 is a water-soluble, semisynthetic derivative of camtothecin. CPT-11 shows its anticancer activity by inhibiting topoisomerase I activity, now a target of anticancer agents with major interest. Recent clinical trials reveal that CPT-11 is very effective in the treatment of cancer including lung cancer, cervical cancer, ovary cancer, stomach cancer, colon cancer, and non-Hodgkin's lymphoma. Major dose limiting toxicities are leukopenia and diarrhea, and are dose related. Topotecan is an another semisynthetic derivative of camtothecin and is also topoisomerase I inhibitor. Topotecan has undergone phase I clinical evaluations in USA, europe, and recently in Japan. DLF are leukopenia and neutropenia. Topotecan is more hydrophilic than its parent compound and shows lesser protein binding. Renal excretion appears to be the major route of elimination. Sobuzoxane (MST-16) is a unique derivative of dioxopiperazine, an inhibitor of topoisomerase II. In phase II studies, definite anticancer effects are observed in patients with non-Hodgkin's lymphoma and adult T-cell leukemia/lymphoma. Responses are seen even in pretreated cases. Leukopenia is also dose-limiting. Non-hematologic toxicities are mild and include alopecia and G.I. toxicities. NC-190 is a novel benzophenazine derivative with excellent antitumor activities against murine tumors. NC-190 also inhibits topoisomerase II. Now the drug is an early clinical phase II studies in Japan. Toxicities include bone marrow suppression, transient mild to moderate liver enzyme elevation, alopecia and mild G.I. toxicities. Tumor responses are occasionally encountered. IST-622 is a semisynthetic derivative of chartreusin. The drug is an inhibitor of topoisomerase II (and I in high concentration). IST-622 shows excellent, broad anticancer activity against murine tumors. The drug is well absorbed from small intestine. IST-622 is now in phase I clinical trial in Japan.
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PMID:[Topoisomerase inhibitors developing in Japan]. 842 86

After failing to exhibit benefits in clinical studies with cancer patients in the early 1970s, camptothecin (CPT) and its water-insoluble analogues are re-emerging as promising drugs with multiple actions in the treatment of human haematological malignancies. CPT analogues interfere with the mechanism of action of the nuclear enzyme topoisomerase I, while the cells progress through the S-phase of the cell cycle and this results in cell death by apoptosis. Modulations of topoisomerase I phosphorylation may indirectly modulate the cytotoxic activity of CPT analogues. In vitro, CPT analogues have exhibited increased or unaltered killing activity against leukaemia cells resistant to epipodophyllotoxins, anthracyclines, anthracenediones, and Vinca alkaloids, while development of resistance to CPT analogues renders leukaemia and lymphoma cells more sensitive to topoisomerase II-directed drugs, inducers of cell differentiation, and immunotoxins. Oral administration of the CPT analogues has circumvented the inconvenience of solubility of these drugs. Metabolic conversion of the CPT analogue 9-nitro-CPT to equally or more potent 9-amino-CPT practically makes unnecessary treatment of the patient with 9-amino-CPT, which, in addition, is costlier to prepare than 9-nitro-CPT. Considering the therapeutic, economic and handling viewpoints, the overall conclusion is that the water-insoluble CPT analogues are very promising antileukaemia/antilymphoma agents that warrant further preclinical and clinical studies.
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PMID:The water-insoluble camptothecin analogues: promising drugs for the effective treatment of haematological malignancies. 855 94

Camptothecin (CPT), an alkaloid isolated from the stem wood and bark of Camptotheca acuminata native to China, was discovered in the early 60's after a systematic screening of natural products by the National Cancer Institute (NCI). This new anticancer agent displays an unique mechanism of action as it inhibits intranuclear enzyme topoisomerase 1, involved in DNA replication. CPT is poorly water soluble and causes severe and unpredictable toxicities such as haemorrhagic cystitis and diarrhea; for therefore reason, a number of analogues have been synthetized in a attempt to define the features of the molecule that are essential for cytotoxicity and to produce derivatives with increased solubility. Clinical trials of several soluble molecules are in progress in the different countries: irinotecan, topotecan, 9-AC. Encouraging results are observed against solid tumors. Irinotecan was recently commercialized in France. It is a prodrug; the active metabolite SN-38 showed a good activity in metastatic colorectal adenocarcinoma; the limiting toxicities are myelotoxicity and essentially late diarrhea. However, new studies are needed for state precisely the optimal schedule of administration and association with other chemotherapeutic agents.
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PMID:[Camptothecin and derivatives: a new class of antitumor agents]. 896 50

Vaccinia topoisomerase forms a covalent protein-DNA intermediate at sites containing the sequence 5'-CCCTT. The T nucleotide is linked via a 3'-phosphodiester bond to Tyr-274 of the enzyme. Here, we report that the enzyme catalyzes hydrolysis of the covalent intermediate, resulting in formation of a 3'-phosphate-terminated DNA cleavage product. The hydrolysis reaction is pH-dependent (optimum pH = 9.5) and is slower, by a factor of 10(-5), than the rate of topoisomerase-catalyzed strand transfer to a 5'-OH terminated DNA acceptor strand. Mutants of vaccinia topoisomerase containing serine or threonine in lieu of the active site Tyr-274 form no detectable covalent intermediate and catalyze no detectable DNA hydrolysis. This suggests that hydrolysis occurs subsequent to formation of the covalent protein-DNA adduct and not via direct attack by water on DNA. Vaccinia topoisomerase also catalyzes glycerololysis of the covalent intermediate. The rate of glycerololysis is proportional to glycerol concentration and is optimal at pH 9.5.
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PMID:DNA strand transfer reactions catalyzed by vaccinia topoisomerase: hydrolysis and glycerololysis of the covalent protein-DNA intermediate. 915 7

pH-mediated conversions in the structure of the topoisomerase (topo) I inhibitors camptothecin (CPT) and its analogues have strong implications for the pharmacokinetics and pharmacodynamics of these novel anticancer agents. Because the cell-penetrating and biologically active lactone isomers predominate at acidic conditions, we have tested if low pH potentiates the cytotoxic and antitumor effects of CPT and its water-soluble derivative topotecan (TPT). In L1210 leukemia cells, rapid initial uptake of radiolabeled CPT and TPT was followed by a gradual release from cells at physiological pH 7.4, whereas high drug levels were maintained in cells at pH 6.2. Steady-state uptake levels of CPT increased proportionally, up to 5-fold, with decreasing pH of the incubating medium (from 7.4 to 6.0). With TPT, a maximum 3-fold increase was observed at pH 6.8 to 6.4. By contrast, the cellular pharmacokinetics of the topoisomerase II inhibitor etoposide (ETP) were independent of the ambient pH. The large increases in intracellular CPT and TPT levels caused only moderate potentiation of cytotoxicity in short-term incubations. Conditions of very low pH < or =6.2 even antagonized the cytotoxicity of the topo I and topo II inhibitors, due to inhibition of DNA synthesis by intracellular acidification. However, in clinically relevant schedules of prolonged exposures at low drug concentration, low pH potentiated the cytotoxicity of CPT and TPT by 2-3-fold. To investigate the effect of local pH in vivo, the basal interstitial pH of 6.8 of RIF-1 tumors was selectively lowered by i.p. injection of the host animals with the mitochondrial inhibitor meta-iodobenzylguanidine (32 mg/kg) and glucose (1.5 g/kg). In accordance with the pH optimum for TPT uptake at pH 6.8 to 6.4, tumor acidification had no effect on the antitumor effect of this analogue. By contrast, the intervention significantly potentiated the response of tumors to CPT. The results indicate that local pH is an important determinant of the cellular pharmacokinetics and the antitumor activity of CPT and analogues.
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PMID:Cellular pharmacokinetics and cytotoxicity of camptothecin and topotecan at normal and acidic pH. 935 43

The mechanisms underlying the circadian rhythm of the toxicity induced by irinotecan hydrochloride (CPT-11; 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) were investigated from the viewpoint of the sensitivity of living organisms and the pharmacokinetics of the drug. ICR male mice were housed under standardized light-dark cycle conditions (lights on at 0700, off at 1900) with food and water ad libitum. The loss of body weight after an intraperitoneal injection of CPT-11 (100 mg/kg) was more serious in the late dark and the early light and milder in the late light and the early dark. The CPT-11-induced leukopenia was more serious in the late dark and milder in the late light. The lower toxicity of CPT-11 was observed when DNA synthesis and type I DNA topoisomerase activity in bone marrow cells decreased and the higher toxicity was observed when these activities began to increase. There were circadian stage-dependent changes in the concentrations of CPT-11 and its major metabolite (SN-38; 7-ethyl-10-hydroxycamptothecin) in plasma. The higher concentrations of CPT-11 and SN-38 in plasma were observed when the level of CPT-11-induced toxicity increased. The present study suggests that the toxicity of CPT-11 is influenced by circadian rhythm-dependent processes.
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PMID:Cell cycle-dependent chronotoxicity of irinotecan hydrochloride in mice. 940 14

A simple and efficient method for the dissection of (marker) chromosomes, (micro)nuclei, and chromosome regions is presented. Before microdissection, metaphases are overlaid with milli-Q water to rehydrate the chromosomes, which makes them soft and sticky. The dissected chromosome fragments are dissolved without proteinase-K or topoisomerase treatment and directly amplified using a degenerate oligonucleotide primed polymerase chain reaction (DOP-PCR). The advantages of this microFISH method over previously reported methods are: (1) microdissection in this way is very fast; (2) a chromosome, marker, (micro)nucleus, or chromosome region is collected as a whole using only one microneedle; (3) the dissected material sticks tightly to the needle without the risk of getting lost; (4) no Sequenase is used in the DOP-PCR reaction which reduces the risk of contamination.
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PMID:A simple and efficient method for microdissection and microFISH. 959 16

New members of the cytotoxic indolo[2,3-b]quinoline family, with a methyl groups at N-5, N-6 (their presence stabilizes the positive charge of the molecule), were prepared using a modified Graebe-Ullmann reaction. The derivatives obtained were well soluble in water in a non-pH-dependent manner. They displayed strong antimicrobial activity against Gram-positive bacteria and pathogenic fungi (the MIC values fall between 0.0025 and 0.12 mM) and highly selective cytotoxicity in vitro against different human cancer cell lines: colon adenocarcinoma SW 707, lung carcinoma A 549, transitional cell carcinoma Hu 1703, and oral epidermoid carcinoma KB, in the range of 0.01 to 3.0 microM. They also stimulated the formation of topoisomerase-II-mediated DNA cleavage at concentration from 0.04 to 0.5 microM. These observations correspond well with the ability of the tested compounds to increase the melting temperature of calf thymus DNA (delta Tm being between 13 degrees C and 22 degrees C).
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PMID:Methoxy- and methyl-, methoxy-5,6,11-trimethyl-6H-indolo [2,3-b]quinolinium derivatives as novel cytotoxic agents and DNA topoisomerase II inhibitors. 971 22

Preclinical and clinical studies have documented the pharmacological interest in camptothecin derivatives in the treatment of resistant tumors. In particular, topotecan, a water-soluble derivative, exhibited promising activity in pretreated ovarian carcinoma. The present study investigated the pattern of tumor response in two human ovarian carcinoma xenografts and in their cisplatin-resistant sublines characterized by different mechanisms of drug resistance. In IGROV-1/Pt1 cells, cisplatin resistance has been ascribed to a reduced susceptibility to apoptosis as a consequence of p53 mutation and inactivation of its function. In the A2780 cisplatin-resistant subline, which retained the wild-type p53 gene status, the development of resistance has been possibly related to increased cell ability to repair drug-induced DNA damage. The in vivo results of the present study showed that topotecan could overcome the resistance in A2780/CP but not in IGROV-1/Pt1 tumor xenografts. The pattern of tumor response following in vivo topotecan treatment correlated with drug ability to induce apoptosis but not with its in vitro antiproliferative activity. The antitumor efficacy of topotecan in the four tumors reflected a different cell response to drug-induced DNA damage, as suggested by different perturbations of cell cycle progression. Indeed, only in the subline refractory to topotecan in vivo, IGROV-1/Pt1, did we observe a persistent arrest of the cells in the S-phase, resulting in a cytostatic and not a cytotoxic effect, since a low level of apoptosis was induced by the drug. In conclusion, the current results support that determination of drug-induced apoptosis is a useful predictor of tumor response to topotecan in ovarian carcinomas and suggest that p53 gene status may be a critical determinant of cell response to topoisomerase inhibitors.
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PMID:Apoptosis as a determinant of tumor sensitivity to topotecan in human ovarian tumors: preclinical in vitro/in vivo studies. 981 71


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