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)

Copper is an essential trace element and several copper containing proteins are indispensable for such processes as oxidative respiration, neural development and collagen remodeling. Copper metabolism is precisely regulated by several transporters and chaperone proteins. Copper Transport Protein 1 (CTR1) selectively uptakes copper into cells. Subsequently three chaperone proteins, HAH1 (human atx1 homologue 1), Cox17p and CCS (copper chaperone for superoxide dismutase) transport copper to the Golgi apparatus, mitochondria and copper/zinc superoxide dismutase respectively. Defects in the copper transporters ATP7A and ATP7B are responsible for Menkes disease and Wilson's disease respectively. These proteins transport copper via HAH1 to the Golgi apparatus to deliver copper to cuproenzymes. They also prevent cellular damage from an excess accumulation of copper by mediating the efflux of copper from the cell. There is increasing evidence that copper transport mechanisms may play a role in drug resistance. We, and others, found that ATP7A and ATP7B are involved in drug resistance against the anti-tumor drug cis-diamminedichloroplatinum (II) (CDDP). A relationship between the expression of ATP7A or ATP7B in tumors and CDDP resistance is supported by clinical studies. In addition, the copper uptake transporter CTR1 has also been reported to play a role in CDDP sensitivity. Furthermore, we have recently found that the effect of ATP7A on drug resistance is not limited to CDDP. Using an ex vivo drug sensitivity assay, the histoculture drug response assay (HDRA), the expression of ATP7A in human surgically resected colon cancer cells correlated with sensitivity to 7-ethyl-10-hydroxy-camptothecin (SN-38). ATP7A-overexpressing cells are resistant to many anticancer drugs including SN-38, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11), vincristine, paclitaxel, etoposide, doxorubicin (Dox), and mitoxantron. The mechanism by which ATP7A and copper metabolism modulate drug transport appears to involve modulation of drug cellular localization via modulation of the vesicle transport system. In ATP7A overexpressing cells, Dox accumulates in the Golgi apparatus. In contrast, in the parental cells, Dox is localized in the nuclei, where the target molecules of Dox, topoisomerase II and DNA, are found. Disruption of the intracellular vesicle transport system with monensin, a Na+/H+ ionophore, induced the relocalization of Dox from the Golgi apparatus to the nuclei in the ATP7A overexpressing cells. These data suggested that ATP7A-related drug transport is dependent on the vesicle transport system. Thus copper transport systems play important roles in drug transport as well as in copper metabolism. Components of copper metabolism are therefore likely to include target molecules for the modulation of drug potency of not only anti-cancer agents but also of other drugs.
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PMID:Copper transport systems are involved in multidrug resistance and drug transport. 1907 68

It is important to clarify the molecular characteristics of tumor cells showing multidrug resistance (MDR) and to identify the novel targets or biomarkers for chemotherapy. The aim of this study is to establish resistant HeLa sublines through exposure to SN-38, an active metabolite of irinotecan hydrochloride, and to investigate their molecular changes. HeLa cells were exposed to SN-38 at 1, 10, or 100 nM, and resistant clones were isolated and named HeLa/SN1, HeLa/SN10, and HeLa/SN100, respectively. Their cellular changes were examined based on growth inhibition assays, the function of ABCG2/BCRP, and a RT-PCR analysis of MDR-related protein. The sublines showed a decrease in sensitivity to not only SN-38 but also other chemotherapeutic agents as compared with HeLa cells. mRNA and protein levels of ABCG2/BCRP were increased, and the transport activity of ABCG2/BCRP was enhanced, in the resistant cells. In addition, the expression levels of ABCC1/MRP1, ABCC3/MRP3, and ABCC5/MRP5 were higher than in HeLa cells. The mRNA levels of GGT1 encoding a gamma-glutamyl transferase, but not GCS encoding a gamma-glutamyl cysteine synthetase, were also higher. Other factors examined, i.e., topoisomerase, SLCO1B1, and apoptosis-regulating factors, were comparable among the cells. The overexpression of ABCG2/BCRP was involved in the mechanism of resistance in SN-38-tolerant cells, and ABCC1/MRP1, ABCC3/MRP3, ABCC5/MRP5, and GGT1 may also have participated.
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PMID:Molecular changes to HeLa cells on continuous exposure to SN-38, an active metabolite of irinotecan hydrochloride. 1920 Oct 79

Cryptosporidium parvum, one of the most important causative organisms of human diarrheas during childhood, contains a monomeric DNA-topoisomerase IB (CpTopIB) in chromosome 7. Heterologous expression of CpTopIB gene in a budding yeast strain lacking this activity proves that the cryptosporidial enzyme is functional in vivo. The enzymatic activity is comprised in a single polypeptide, which contains all the structural features defining a fully active TopIB. Relaxation activity of the yeast extracts was detected only when CpTopIB ORF was expressed in a yeast expression system showing time and protein dependence under steady state kinetic conditions. The susceptibility of CpTopIB-transformed yeast to the irreversible inhibitor camptothecin and its water-soluble derivatives (topotecan and SN-38) was assessed.
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PMID:Functional expression of a DNA-topoisomerase IB from Cryptosporidium parvum. 1964 60

Genetic variation in the receptors and other intracellular targets that mediate the pharmacodynamic effects of drugs can affect therapeutic outcomes. However, at present greater knowledge is available concerning the extent of gene variation in drug metabolizing enzymes that determine drug pharmacokinetics and, in turn, drug efficacy and toxicity. Information on the incidence of polymorphisms in the cytochrome P450 (CYP) genes that mediate phase I biotransformation is increasing, although the level of detail in the case of phase II conjugation enzymes, such as the UDP-glucuronosyltransferases (UGTs) and N-acetyltransferases (NATs), is not as extensive. It is now apparent that defective alleles that encode variant CYPs, UGTs, NATs and other biotransformation enzymes can influence the outcome of therapy. Diminished rates of drug clearance can increase the incidence of toxicity from many drugs, but may also enhance efficacy, as in the case of the proton-pump inhibitor omeprazole, that maintains therapeutic serum concentrations in individuals that carry null alleles for CYP2C19. Variant alleles of UGT1A1 are less capable of conjugating and eliminating SN-38, the active form of the topoisomerase inhibitor irinotecan, and defective alleles for NAT2 are responsible for the well-described acetylation polymorphism that leads to impaired clearance of isoniazid and other agents. This review focuses on reports that relate pharmacogenetic variation in phase I and phase II enzymes to the safety and toxicity of drug therapy and highlights a number of themes that have emerged recently that may be developed to streamline therapy for individuals.
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PMID:Pharmacogenetics of phase I and phase II drug metabolism. 1983 60

Neural stem cells (NSCs) have been investigated in preclinical models as delivery vehicles for therapeutic genes for treatment of tumors in the central nervous system and other organs. Melanoma at early stages is effectively treated with surgery and radiotherapy, however metastatic disease is almost universally fatal, thus novel therapeutic approaches are needed. We studied the use of HB1.F3.CD therapeutic NSCs, a well-characterized clonal cell line derived from human fetal telencephalon, for their potential of secreting prodrug-activating enzyme. HB1.F3.CD cells were transduced by adenovirus encoding rabbit carboxylesterase (rCE), which converts CPT-11 into SN-38, a potent topoisomerase 1 inhibitor. In vitro cell migration assays revealed robust migration of NSCs to conditioned media from melanoma cells. Cytokine profiles showed that IL-6, IL-8, MCP-1 and TIMP-2, known chemoattractants for stem cells, were highly expressed by melanoma cells. Exposure of melanoma cells to conditioned media from the HB1.F3.CD.rCE cells in the presence of CPT-11 increased the tumor cell-killing effect by approximately 100-fold when compared to CPT-11 alone. Our data demonstrate the rational for NSC-based enzyme/prodrug therapeutic approach to target metastatic melanoma. Future experiments will evaluate the therapeutic efficacy of NSC-mediated melanoma therapy in animal models, which will provide the basis for targeted therapy in patients with advanced melanoma.
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PMID:Therapeutic targeting of melanoma cells using neural stem cells expressing carboxylesterase, a CPT-11 activating enzyme. 1995 Dec 51

A goal of oncology is to predict chemosensitivity of tumors. This approach assumes that in a patient all tumor deposits are homogeneous. We have tested the heterogeneity between several samples of the same liver metastasis (LM; intrametastatic heterogeneity) or between multiple LM (intermetastatic heterogeneity) from colorectal cancer in a single patient. In 16 untreated patients, several fragments of LM and nontumorous liver were collected. Heterogeneity to anticancer drug treatment was assessed in vitro on primary tissue cultures on poly-HEMA-coated surface with or without the topoisomerase-I inhibitor metabolite SN-38. Heterogeneity of response to SN-38 was observed in 55% of cases from one fragment to another in the same LM and in 64% of cases from one LM to another in the same patient. Allelic losses were characterized on 5q, 8p, 17p, 18q, 22q using 29 microsatellites markers. Seven patients (58%) had a perfect homogeneity for allelic losses in their LM whereas 3 (21%) had intrametastatic and 2 (18%) had intermetastatic heterogeneity. The analysis of gene expression was carried out by real time RT-PCR quantification using specific probes for TS, TOPO1, ERCC1, and CES2. Level expression of genes tested appeared heterogeneous with average variations of 57(+ or - 23)%, 52(+ or - 18)%, 53(+ or - 18)%, 56(+ or - 16)% for TS, TOPO1, ERCC1, and CES2 respectively for intermetastatic variability and 47(+ or - 26)%, 36(+ or - 14)%, 38(+ or - 19)%, and 56(+ or - 29)%, respectively for intrametastatic variability. Our results demonstrate intermetastatic and intrametastatic heterogeneity suggesting that pretherapeutic analysis of a single tumor biopsy is likely to lead to a misinterpretation of sensitivity to anticancer treatment.
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PMID:Evidence of heterogeneity within colorectal liver metastases for allelic losses, mRNA level expression and in vitro response to chemotherapeutic agents. 2001 40

CPT-11, a derivative of camptothecin (CPT) that interacts with type-I DNA topoisomerase, induced apoptosis in HL60 and Daudi cells in vitro. This cytotoxic activity was time and dose dependent, and was prevented by cycloheximide (CHX), a protein synthesis inhibitor, indicating the requirement of new protein synthesis for CPT-11-induced apoptotic cell death. Ac-Tyr-Val-Ala-Asp-aldehyde (YVAD) and Ac-Asp-Glu-Val-Asp-aldehyde (DEVD), synthesized tetrapeptide inhibitors of interleukin(1beta)-converting enzyme (ICE)- and CPP32/Yama-like proteases, were used to examine the CPT-11-induced death signal transduction. These inhibitors blocked CPT-11-induced cytotoxicity in a time- and dose-dependent manner. Cytotoxic activity of SN-38, an active metabolite of CPT-11, was about 1000-fold that of CPT-11 and was also prevented by CHX, YVAD and DEVD. The doses of YVAD, however, were a little too high; the prevention by YVAD is then thought to be non-specific. In addition, lymphocytes obtained from normal and lpr(cg) mutant mice showed similar susceptibility to CPT-11 cytotoxicity. These results indicate the direct involvement of CPP32/Yama-like protease in the CPT-11-induced death signal transduction pathway, and no involvement of Fas antigen in the pathway.
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PMID:Involvement of CPP32/Yama-like protease in CPT-11-induced death signal transduction pathway. 2065 Feb 53

N-aminomethyl-1H-benzimidazole-5-carboxylic acid derivatives 2-5 and the ligand, 1-(5 (or 6-)-carboxy-1H-benzimidazol-2-ylmethyl)pyridinium chloride (6; H2L1) have been synthesized. New benzimidazole complexes 7-9 of the ligand 6; H2L1 with Cu2+, Co2 and Zn2+ were prepared. The growth-inhibitory against a panel of 21 human cancer cell lines of the synthesized compounds 1-9 was studied. Compounds 6-9 showed potent growth-inhibitory activity against the studied cell lines. The correlation coefficients according to COMPARE analysis of the National Cancer Institute screening protocol showed that the pattern of the growth-inhibitory effect of the compounds 6-9 was similar to that of etoposide and doxorubicin but different from that of SN-38 and cisplatin. The topoisomerase II inhibitory activity of the tested compounds 6-9 was studied. Compounds 6 and 8 inhibited topoisomerase II activity at 10 times lower concentration than etoposide in relaxation assay.
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PMID:Synthesis and antitumor activity of novel benzimidazole-5-carboxylic acid derivatives and their transition metal complexes as topoisomerease II inhibitors. 2088 89

Topoisomerase I inhibitors have shown positive effects in combination with radiation therapy in some studies. Normally oxygenated and hypoxic human MCF-7 breast carcinoma-cells were exposed to irinotecan (100 mu M or 250 mu M) or to SN-38 (10 mu M or 25 mu M) for 1 h prior to, during and for 3 h after radiation. Irinotecan and SN-38 showed little or no radiation sensitization of normally oxygenated MCF-7 cells but were effective radiation sensitizers of hypoxic cells. Both irinotecan and SN-38 diminished or eliminated the shoulder of the radiation survival curves of both the normally oxygenated and hypoxic cells indicating inhibition of the repair of sublethal radiation damage to DNA. Irinotecan (20 mg/kg or 30 mg/kg) was administered to mice bearing the EMT-6 mammary carcinoma on days 7 through 11 just prior to fractionated radiation (5x3 Gray). The tumor growth delays obtained with the combination regimens were greater than expected for simple additivity of the two treatments. Treatment with irinotecan resulted in decreased expression of topoisomerase I mRNA and increased expression of topoisomerase II mRNA in EMT-6 tumor tissue. Irinotecan treatment did not alter the protein levels for topoisomerase I or II in the tumor tissue; however, the combination of radiation therapy and irinotecan administration resulted in decreased topisomerase I and increased topoisomerase II protein in the tumor tissue. These results suggest that with appropriate scheduling of a topoisomerase I inhibitor and a topoisomerase II inhibitor with fractionated radiation therapy maximal cyto-reduction can be achieved.
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PMID:Irinotecan and radiation in vitro and in vivo. 2152 28

Irinotecan Hydrochloride (CPT-11) and 7-ethyl-10-hydroxycamptothecin (SN-38), which are both topoisomerase I inhibitors with potent antitumor effects in vivo and in vitro, were tested for the induction of programmed cell death (PCD) in leukemia/lymphoma cell lines. When the human T-cell leukemia cell line HUT-102 and the human promyelocytic leukemia cell line HL-60 cells were exposed to CPT-11, PCD characterized by a DNA fragmentation ladder of 180-200 bp in agarose gel electrophoresis and loss of cell viability was induced. The PCD inducing activity of SN-38, an active metabolite of CPT-11, was much more powerful than that of CPT-11. Besides inducing PCD in HUT-102 and HL-60 cells, SN-38 also induced PCD in the human erythroblast leukemia cell line K-562, which was resistant to CPT-11. Induction of PCD by SN-38 and CPT-11 was dose- and time-dependent. PCD in HUT-102 cells induced by SN-38 was prevented neither by aurintricarboxylic acid (ATA), an endonuclease inhibitor, as determine by DNA electrophoretic profiles and the number of viable cells, nor by the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA). The present data suggest that the topoisomerase I inhibitors, SN-38 and CPT-11 exert antitumor activity through induction of PCD in involved cells, at least in part. The PCD-inducing activity of the topoisomerase II inhibitor VP-16 was also tested in the above three cell lines and compared with CPT-11 and SN-38.
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PMID:A new derivative of camptothecin, irinotecan hydrochloride (cpt-11) induces programmed cell-death in leukemia-lymphoma cell-lines. 2157 18


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