Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of compounds structurally related to staurosporine, rebeccamycin, and corresponding aglycones was synthesized, and their activities toward protein kinase C and topoisomerases I and II were tested together with their in vitro antitumor efficiency against murine B16 melanoma and P388 leukemia cells. Their antimicrobial activities were also examined against a Gram-negative bacterium (Escherichia coli), a yeast (Candida albicans), and three Gram-positive bacteria (Bacillus cereus, Streptomyces chartreusis, and Streptomyces griseus). To avoid side effects expected with protein kinase C inhibitors, we introduced substitution on the maleimide nitrogen and/or a sugar moiety linked to one of the indole nitrogens to obtain specific inhibitors of topoisomerase I with minimal activities on protein kinase C. As expected, these structures were inefficient on topoisomerase II, and some of them exhibited a strong activity against topoisomerase I. Generally, dechlorinated compounds were found to be more active than chlorinated analogues against both purified topoisomerase I and protein kinase C. On the other hand, opposite results were obtained in the cell antiproliferative assays. These results suggest lack of cell membrane permeability in the absence of the chlorine residue or cleavage of carbon-chlorine bonds inside the cell.
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PMID:Structure-activity relationships in a series of substituted indolocarbazoles: topoisomerase I and protein kinase C inhibition and antitumoral and antimicrobial properties. 889 41

A fluorescence image cytometry technique was developed to measure the effects of topotecan, a topoisomerase I inhibitor, on the nuclear expression of topoisomerase II alpha in a series of patients with refractory or relapsed acute myeloid leukemia (AML). We used a commercially available affinity-purified rabbit polyclonal antibody and a fluorescein-conjugated secondary antibody. By using DAPI as a DNA counterstain and dual wavelength excitation, it was possible to measure enzyme expression in the cell nucleus, and to examine its cell cycle phase distribution. In human acute leukemia cell lines, topoisomerase II alpha expression was greatest in late S and G2 phases, but in leukemia patient samples the enzyme expression appeared to be much less cell cycle dependent. There was considerable interpatient variation in the effects of topotecan on topoisomerase II alpha expression in the leukemia patients, with a threefold increase in the median value after 48 h followed by a decline to pretreatment levels after 5 days of treatment with the topoisomerase I inhibitor. Although these findings should be treated with caution because of the small number of cases studied, they support the prediction that topoisomerase I inhibitors might be capable of increasing sensitivity to topoisomerase II active drugs such as anthracyclines and epipodophyllotoxins by upregulating topoisomerase II expression. They also illustrate the potential value of fluorescence image cytometry for making sequential measurements of the effects of drug resistance modulating agents in cancer patients.
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PMID:Effects of topoisomerase I inhibition on the expression of topoisomerase II alpha measured with fluorescence image cytometry. 891 17

Camptothecin resistance of the human leukemia CEM/C2 cells is associated with a topoisomerase I (top1) mutation: Asn722Ser (Fujimori, A. et al. Cancer Res. 55:1339-1346; 1995). The corresponding DNA point mutation generates a novel site for the restriction endonuclease DdeI. We found that only the mutated top1 transcript was detectable in CEM/C2 by reverse transcriptase-polymerase chain reaction. Genomic DNA analysis by Southern blotting with DdeI showed that both the mutated and normal top1 genes were present in CEM/C2 cells. The mechanism of normal top1 allele silencing was further investigated. Cytogenetic analysis with a human chromosome 20 specific probe and restriction mapping by Southern blotting showed that both cell lines had a similar copy number of chromosome 20, with the predominant population containing 5-6 copies, and no detectable top1 gene rearrangement. Southern blotting using methylcytosine-sensitive restriction endonuclease (HpaII) indicated differential top1 methylation in CEM/C2 cells. Global cytosine methylation, however, appeared similar in CEM/C2 and wild-type CEM cells. These results indicate that gene-specific DNA methylation can play a role in downregulating top1 gene(s) and in the cellular resistance to camptothecins.
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PMID:Silencing and selective methylation of the normal topoisomerase I gene in camptothecin-resistant CEM/C2 human leukemia cells. 893 93

Topotecan (TPT) is a topoisomerase I (topo I) poison that has shown promising antineoplastic activity in solid tumors and acute leukemia. In the present study, a band depletion assay was used to evaluate the ability of TPT to stabilize topo I-DNA adducts in human leukemia cell lines and in clinical leukemia samples ex vivo. This assay showed that 50% of the cellular topo I in HL-60 human myelomonocytic leukemia cells became covalently bound to DNA at an extracellular TPT concentration of 4 micromol/L. In contrast, in 13 clinical specimens of human leukemia harvested before treatment of patients with TPT, the TPT concentration required to stabilize 50% of the cellular topo I in topo I-DNA complexes ranged from 3 to greater than 100 micromol/L (median, 30 micromol/ L). Flow microfluorimetry showed that cellular TPT accumulation varied over only a twofold range and failed to provide evidence for transport-mediated resistance in the clinical samples. These observations raise the possibility that formation of topo I-DNA adducts is diminished in many specimens of refractory/relapsed acute leukemia by a mechanism that might alter topo I sensitivity to TPT.
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PMID:Altered formation of topotecan-stabilized topoisomerase I-DNA adducts in human leukemia cells. 905 32

The mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) is currently in clinical trial as an anticancer drug. A series of acridine-substituted analogues were prepared, using a new synthetic route to substituted acridine-4-carboxylic acids (conversion of substituted diphenylamine diacid monoesters to the corresponding aldehydes and mild acid-catalyzed ring closure to form the acridines directly). The analogues were evaluated in a panel of cell lines which included wild-type (JLC) and mutant (JLA and JLD) forms of the human Jurkat leukemia line. The latter mutant lines are resistant to topoisomerase II targeted agents due to lower levels of the enzyme. Structure-activity studies suggest that the electronic properties of the substituents do not markedly affect cytotoxicity, but steric bulk is important, with larger groups leading to loss of activity. The compounds fell broadly into two categories. The majority had cytotoxicities similar to (or lower than) that of DACA itself and were equitoxic in all the Jurkat lines, suggesting a relatively greater effect on topoisomerase I compared with topoisomerase II. Most of the 5-substituted derivatives and the 7-Ph compound were more cytotoxic than DACA, but were less effective against JLA and JLD cell lines than in the wild-type JLC, suggesting a mode of cytotoxicity largely mediated by effects on topoisomerase II. Both DACA and selected acridine-substituted analogues were active in the relatively refractory subcutaneous colon 38 tumor model in vivo.
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PMID:Structure-activity relationships for acridine-substituted analogues of the mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide. 919 70

The mechanisms involved in the restriction of the cellular tropism of HIV-1 to cells of primate origin remain to be clearly defined. However, a number of studies have shown that this is determined not only at the level of the cellular receptor(s) or virus entry, but at a number of additional and later stages in virus replication. We have recently reported that the reverse transcription of HIV-1 RNA is markedly enhanced by the association of the gag encoded nucleocapsid p15 protein and cellular topoisomerase 1. In the present study we have now investigated if the recruitment of cellular topoisomerase I during virus replication is important in determining the cellular tropism of HIV-1. Employing a stable murine cell line, L929, expressing both human CD4 and topoisomerase I, it could be demonstrated that effective proviral DNA synthesis occurred following infection. In contrast in cells expressing only human CD4 proviral DNA synthesis was not detected. In addition we have co-expressed fusin, a protein known to act as an accessory factor as the virus entry stage in infection of T cell tropic HIV-1, to support viral entry completely. However no progeny virus could be detected after HIV-1 infection. These results suggest that reverse transcription in vivo is critically dependent on the presence of cellular topoisomerase I, and support the view that involvement of this enzyme is in HIV-1 replication. Moreover the findings suggest that other factors which remained to be identified, are involved in restricting HIV-1 replication in non-primate cells.
Leukemia 1997 Apr
PMID:The role of topoisomerase I in HIV-1 replication. 920 86

The mechanisms involved in the restriction of the cellular tropism of HIV-1 to cells of primate origin remain to be clearly defined. However, a number of studies have shown that this is determined not only at the level of the cellular receptor(s) or virus entry, but at a number of additional and later stages in virus replication. We have recently reported that the reverse transcription of HIV-1 RNA is markedly enhanced by the association of the gag encoded nucleocapsid p15 protein and cellular topoisomerase I. In the present study we have investigated if the recruitment of cellular topoisomerase I during virus replication is important in determining the cellular tropism of HIV-1. Employing a stable murine cell line, L929, expressing both human CD4 and topoisomerase I, it could be demonstrated that effective proviral DNA synthesis occurred following infection. In contrast in cells expressing only human CD4, proviral DNA synthesis was not detected. In addition we have co-expressed fusin, a protein known to act as an accessory factor as the virus entry stage in infection of T cell tropic HIV-1, to support viral entry completely. However no progeny virus could be detected after HIV-1 infection. These results suggest that reverse transcription in vivo is critically dependent on the presence of cellular topoisomerase I, and support the view that involvement of this enzyme is important in HIV-1 replication. Moreover the findings suggest that other factors which remained to be identified, are involved in restricting HIV-1 replication in non-primate cells.
Leukemia 1997 Apr
PMID:The role of topoisomerase I in HIV-1 replication. 920 15

The human leukemia cell line, HL60 is very sensitive to various apoptotic stimuli and p53-null. The death-related cysteine proteases of the caspases family play a central role in the execution phase of apoptosis, and we recently reported the importance of serine protease activation in camptothecin-induced apoptotic endonuclease activation in HL60 cells. In the present study, we investigated the role of caspases (ICE/CED-3-related cysteine proteases) and serine proteases in cell death induced by the topoisomerase I inhibitor, camptothecin, in HL60 cells and in a cell-free system. We found that CPP32 is activated during camptothecin-induced apoptosis, and that N-benzyloxycarbony-Val-Ala-Asp (O-methyl) -fluoromethyketone (Z-VAD-fmk), a cell permeable caspase inhibitor blocks all features of apoptosis: morphological changes, cleavage of caspase 3 (CPP32/Yama/Apopain) and poly(ADP-ribose) polymerase, lamin B degradation and DNA fragmentation. However, Z-VAD-fmk and two other ICE/CED-3 inhibitors, YVAD-CHO and DEVD-CHO, were inactive in a cell-free system reconstituted from nuclei of untreated HL60 cells and cytosol from camptothecin-treated cells, suggesting that caspases are not required for endonuclease activation or lamin B cleavage in the cell-free system. By contrast, the serine protease inhibitors, 3,4-dichloroisocoumarin (DCI) and L-1-chloro-3-(4-tosylamido)-4-phenyl-2-butanone tosyl-L-phenylalanine chloromethyl ketone (TPCK), abolished the apoptosis-associated biochemical changes induced by camptothecin both in whole cells and in a cell-free system. DCI also inhibited CPP32 cleavage. Taken together, these results suggest that in HL60 cells, both CPP32 and serine proteases are activated in camptothecin-induced apoptosis.
Leukemia 1997 Aug
PMID:Camptothecin-induced apoptosis in p53-null human leukemia HL60 cells and their isolated nuclei: effects of the protease inhibitors Z-VAD-fmk and dichloroisocoumarin suggest an involvement of both caspases and serine proteases. 926 76

As a part of studies on structure-activity relationships, several potential topoisomerase I inhibitors were prepared. Different analogues of the antitumor antibiotic rebeccamycin substituted on the imide nitrogen with a methyl group were synthesized. These compounds bore either the sugar residue of rebeccamycin, with or without the chlorine atoms on the indole moieties, or modified sugar residues (galactopyranosyl, glucopyranosyl, or fucopyranosyl) linked to the aglycone via a beta- or alpha-N-glycosidic bond. Their inhibitory properties toward protein kinase C, topoisomerase I, and topoisomerase II were examined, and their DNA-binding properties were investigated. Their in vitro antitumor activities against murine B16 melanoma and P388 leukemia cells were determined. Their antimicrobial activities were tested against Gram-positive bacteria Bacillus cereus and Streptomyces chartreusis, Gram-negative bacterium Escherichia coli, and yeast Candida albicans. These compounds are inactive toward topoisomerase II but inhibit topoisomerase I. A substitution with a methyl group on the imide nitrogen led to a loss of proteine kinase C inhibition in the maleimide indolocarbazole series but did not prevent topoisomerase I inhibition. Compounds possessing a beta-N-glycosidic bond, which fully intercalated into DNA, were more efficient at inhibiting topoisomerase I than their analogues with an alpha-N-glycosidic bond; however, both were equally toxic toward P388 leukemia cells. Dechlorinated rebeccamycin possessing a methyl group on the imide nitrogen was about 10 times more efficient in terms of cytotoxicity and inhibition of topoisomerase I than the natural metabolite.
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PMID:Syntheses and biological activities (topoisomerase inhibition and antitumor and antimicrobial properties) of rebeccamycin analogues bearing modified sugar moieties and substituted on the imide nitrogen with a methyl group. 934 21

This article reviews the clinical pharmacokinetics of a water-soluble analogue of camptothecin, irinotecan [CPT-11 or 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxy-camptoth eci n]. Irinotecan, and its more potent metabolite SN-38 (7- ethyl-10-hydroxy-camptothecin), interfere with mammalian DNA topoisomerase I and cancer cell death appears to result from DNA strand breaks caused by the formation of cleavable complexes. The main clinical adverse effects of irinotecan therapy are neutropenia and diarrhoea. Irinotecan has shown activity in leukaemia, lymphoma and the following cancer sites: colorectum, lung, ovary, cervix, pancreas, stomach and breast. Following the intravenous administration of irinotecan at 100 to 350 mg/m2, mean maximum irinotecan plasma concentrations are within the 1 to 10 mg/L range. Plasma concentrations can be described using a 2- or 3-compartment model with a mean terminal half-life ranging from 5 to 27 hours. The volume of distribution at steady-state (Vss) ranges from 136 to 255 L/m2, and the total body clearance is 8 to 21 L/h/m2. Irinotecan is 65% bound to plasma proteins. The areas under the plasma concentration-time curve (AUC) of both irinotecan and SN-38 increase proportionally to the administered dose, although interpatient variability is important. SN-38 levels achieved in humans are about 100-fold lower than corresponding irinotecan concentrations, but these concentrations are potentially important as SN-38 is 100- to 1000-fold more cytotoxic than the parent compound. SN-38 is 95% bound to plasma proteins. Maximum concentrations of SN-38 are reached about 1 hour after the beginning of a short intravenous infusion. SN-38 plasma decay follows closely that of the parent compound with an apparent terminal half-life ranging from 6 to 30 hours. In human plasma at equilibrium, the irinotecan lactone form accounts for 25 to 30% of the total and SN-38 lactone for 50 to 64%. Irinotecan is extensively metabolised in the liver. The bipiperidinocarbonylxy group of irinotecan is first removed by hydrolysis to yield the corresponding carboxylic acid and SN-38 by carboxyesterase. SN-38 can be converted into SN-38 glucuronide by hepatic UDP-glucuronyltransferase. Another recently identified metabolite is 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxy-camptothecin (APC). This metabolite is a weak inhibitor of KB cell growth and a poor inducer of topoisomerase I DNA-cleavable complexes (100-fold less potent than SN-38). Numerous other unidentified metabolites have been detected in bile and urine. The mean 24-hour irinotecan urinary excretion represents 17 to 25% of the administered dose. Recovery of SN-38 and its glucuronide in urine is low and represents 1 to 3% of the irinotecan dose. Cumulative biliary excretion is 25% for irinotecan, 2% for SN-38 glucuronide and about 1% for SN-38. The pharmacokinetics of irinotecan and SN-38 are not influenced by prior exposure to the parent drug. The AUC of irinotecan and SN-38 correlate significantly with leuco-neutropenia and sometimes with the intensity of diarrhoea. Certain hepatic function parameters have been correlated negatively with irinotecan total body clearance. It was noted that most tumour responses were observed at the highest doses administered in phase I trials, which indicates a dose-response relationship with this drug. In the future, these pharmacokinetic-pharmacodynamic relationships will undoubtedly prove useful in minimising the toxicity and maximise the likelihood of tumour response in patients.
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PMID:Clinical pharmacokinetics of irinotecan. 934 1


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