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Anti-cancer Drugs Aug 2010Edotecarin (J-107088), a novel inhibitor of topoisomerase I has an additive effect on colon cell lines (HCT-116) when combined with 5-fluorouracil (5-FU). We conducted a... (Randomized Controlled Trial)
Randomized Controlled Trial
Edotecarin (J-107088), a novel inhibitor of topoisomerase I has an additive effect on colon cell lines (HCT-116) when combined with 5-fluorouracil (5-FU). We conducted a phase I study to determine the maximum tolerated dose and recommended a phase II dose of edotecarin in combination with infusional 5-FU/leucovorin (LV) in patients with advanced solid tumors. Patients and cohorts of three to six patients were sequentially enrolled at progressively higher dose levels of edotecarin administered as a 1-h intravenous (IV) infusion every 2 weeks. The edotecarin starting dose was 6 mg/m, followed by 200 mg/m LV IV infusion administered over 2 h, then 400 mg/m bolus dose of 5-FU before the start of 2400 mg/m 5-FU continuous infusion for a further 46 h. Patients were evaluated for safety, pharmacokinetics, and tumor response according to the Response Evaluation Criteria in Solid Tumors criteria. Fourteen patients (10 male; four female) received a total of 90 cycles (range 3-18). Dose-limiting toxicities were observed in five of the 14 patients treated in the study. All dose-limiting toxicities were related to neutropenia. Only the 6 and 8 mg/m edotecarin dose levels were explored; however, no maximum tolerated dose was declared. One confirmed complete response in a patient with hepatocellular carcinoma and seven stable disease responses were achieved in the 14 treated patients. Pharmacokinetic analysis showed that edotecarin achieved and maintained apparent steady-state plasma concentrations during the IV administration in both the cycles. The administration of edotecarin in combination with infusional 5-FU/LV once every 14 days, even without the 5-FU bolus, did not permit adequate time for recovery from neutropenia.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasms; Topoisomerase I Inhibitors
PubMed: 20581657
DOI: 10.1097/CAD.0b013e32833cb658 -
Scientific Reports May 2016A library of arylidenefuropyridinediones was discovered as potent inhibitors of Leishmania donovani Topoisomerase 1 (LdTop1) where the active molecules displayed...
A library of arylidenefuropyridinediones was discovered as potent inhibitors of Leishmania donovani Topoisomerase 1 (LdTop1) where the active molecules displayed considerable inhibition with single digit micromolar EC50 values. This molecular library was designed via intuitive scaffold hopping and bioisosteric modification of known topoisomerase 1 inhibitors such as camptothecin, edotecarin and etc. The design was rationalized by molecular docking analysis of the compound prototype with human topoisomerase 1 (HTop1) and Leishmania donovani topoisomerase 1(LdTop1). The most active compound 4 displayed no cytotoxicity against normal mammalian COS7 cell line (~100 fold less inhibition at the EC50). Similar to camptothecin, 4 interacted with free LdTop1 as observed in the preincubation DNA relaxation inhibition experiment. It also displayed anti-protozoal activity against Leishmania donovani promastigote. Crystal structure investigation of 4 and its molecular modelling with LdTop1 revealed putative binding sites in the enzyme that could be harnessed to generate molecules with better potency.
Topics: Animals; COS Cells; Chlorocebus aethiops; Crystallography, X-Ray; DNA Topoisomerases, Type I; Leishmania donovani; Leishmaniasis, Visceral; Models, Molecular; Protozoan Proteins; Topoisomerase I Inhibitors
PubMed: 27221589
DOI: 10.1038/srep26603 -
Journal of Molecular Graphics &... Nov 2020Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound zinc metallopeptidase that generates the vasodilatory peptide angiotensin 1-7 and thus performs a protective...
Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound zinc metallopeptidase that generates the vasodilatory peptide angiotensin 1-7 and thus performs a protective role in heart disease. It is considered an important therapeutic target in controlling the COVID-19 outbreak, since SARS-CoV-2 enters permissive cells via an ACE2-mediated mechanism. The present in silico study attempted to repurpose existing drugs for use as prospective viral-entry inhibitors targeting human ACE2. Initially, a clinically approved drug library of 7,173 ligands was screened against the receptor using molecular docking, followed by energy minimization and rescoring of docked ligands. Finally, potential binders were inspected to ensure molecules with different scaffolds were engaged in favorable contacts with both the metal cofactor and the critical residues lining the receptor's active site. The results of the calculations suggest that lividomycin, burixafor, quisinostat, fluprofylline, pemetrexed, spirofylline, edotecarin, and diniprofylline emerge as promising repositionable drug candidates for stabilizing the closed (substrate/inhibitor-bound) conformation of ACE2, thereby shifting the relative positions of the receptor's critical exterior residues recognized by SARS-CoV-2. This study is among the rare ones in the relevant scientific literature to search for potential ACE2 inhibitors. In practical terms, the drugs, unmodified as they are, may be introduced into the therapeutic armamentarium of the ongoing fight against COVID-19 now, or their scaffolds may serve as rich skeletons for designing novel ACE2 inhibitors in the near future.
Topics: Amino Acid Motifs; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Antiviral Agents; Betacoronavirus; COVID-19; Carbazoles; Catalytic Domain; Coronavirus Infections; Drug Repositioning; Dyphylline; Host-Pathogen Interactions; Humans; Hydroxamic Acids; Ligands; Molecular Docking Simulation; Pandemics; Paromomycin; Pemetrexed; Peptidyl-Dipeptidase A; Pneumonia, Viral; Protein Binding; Protein Interaction Domains and Motifs; Protein Structure, Secondary; SARS-CoV-2; Small Molecule Libraries; Structure-Activity Relationship; Thermodynamics
PubMed: 32739642
DOI: 10.1016/j.jmgm.2020.107697 -
Croatian Medical Journal Apr 2006We describe the response to a new chemotherapy agent, topoisomerase I inhibitor edotecarin in an 18-year-old woman with recurring glioblastoma. The therapy was...
We describe the response to a new chemotherapy agent, topoisomerase I inhibitor edotecarin in an 18-year-old woman with recurring glioblastoma. The therapy was administered for 17 months. The radiological partial response and clinical improvement have been achieved, with minor toxicity. Median survival of patients with glioblastoma is 10 months. With edotecarin we have achieved promising result, which should encourage further investigations to develop more efficient therapy for such a deadly disease.
Topics: Adolescent; Antineoplastic Agents; Brain Neoplasms; Carbazoles; Combined Modality Therapy; Female; Glioblastoma; Humans; Indoles; Topoisomerase I Inhibitors
PubMed: 16625697
DOI: No ID Found -
Japanese Journal of Cancer Research :... Oct 1999J-107088 (6-N-(1-hydroxymethyl-2-hydroxy)ethylamino-12,13-dihydro-2,10-dihydroxy- 13-(beta-D-glucopyranosyl)-5H-indolo[2,3-a]-pyrrolo [3,4-c]carbazole-5,7(6H)-dione) is...
J-107088 (6-N-(1-hydroxymethyl-2-hydroxy)ethylamino-12,13-dihydro-2,10-dihydroxy- 13-(beta-D-glucopyranosyl)-5H-indolo[2,3-a]-pyrrolo [3,4-c]carbazole-5,7(6H)-dione) is a derivative of NB-506, an indolocarbazole compound previously reported as an anti-tumor agent targeting topoisomerase I. The optimal administration schedule of J-107088 was found to be intermittent injections. The GID75 (75% growth inhibiting total dose) values of J-107088 against LX-1 lung cancer and PC-3 prostate cancer when given by intermittent injection (twice a week for 2 consecutive weeks) were 200 and 15 mg/m2, respectively, whereas the 10% lethal dose (LD10) values of J-107088 against LX-1- and PC-3-bearing mice were 578 and 1200 mg/m2. The ratio of LD10/GID75 indicates the therapeutic window of an anti-tumor agent. Although the ratios of doxorubicin, paclitaxel and cisplatin against PC-3 were <0.3, <0.5 and <0.2, J-107088 showed the widest therapeutic window among the anti-tumor drugs tested. J-107088 was also effective on cells that had acquired resistance related to P-glycoprotein. Furthermore, J-107088 was found to be highly effective in inhibiting proliferation of micro-metastases of tumors to the liver in mice. Therefore, J-107088 is considered to be a promising candidate as an anti-tumor drug for treatment of solid tumors in humans.
Topics: Animals; Antineoplastic Agents; Body Weight; Breast Neoplasms; Carbazoles; Cisplatin; Colonic Neoplasms; Doxorubicin; Drug Administration Schedule; Female; Glucosides; Humans; Indoles; Leukemia P388; Lung Neoplasms; Male; Mice; Mice, Inbred Strains; Mice, Nude; Neoplasms; Paclitaxel; Prostatic Neoplasms; Time Factors
PubMed: 10595746
DOI: 10.1111/j.1349-7006.1999.tb00691.x -
Oncology Reports Sep 2013Various anticancer drugs, including camptothecins and indolocarbazoles, target DNA topoisomerase I (Top1). We previously described the camptothecin-resistant colon...
Various anticancer drugs, including camptothecins and indolocarbazoles, target DNA topoisomerase I (Top1). We previously described the camptothecin-resistant colon cancer cell line DLDSNR6, which has a Gly365Ser missense mutation in Top1. In the present study, we established highly camptothecin-resistant sublines from DLDSNR6 cells by continuous exposure to higher camptothecin concentrations. The established sublines grew in the presence of 30 µM of camptothecin, but exhibited markedly retarded growth. In addition to Gly365Ser, these sublines harbored a Top1 Gly717Arg mutation and some had also a Top1 Gln421Arg mutation. Top1 activity was reduced to approximately one-eighth in highly resistant cell lines compared with that in parental DLD-1 cells. Resistant clones with 3 Top1 mutations including Gln421RArg exhibited the highest resistance to the indolocarbazole J-107088 in terms of the effect on the cell cycle distribution. The Gln421 mutation was equivalent to a mutation recently found in camptothecin biosynthesizing plants, but it has not previously been found in mammalian cells.
Topics: ATP-Binding Cassette Transporters; Apoptosis; Blotting, Western; Camptothecin; Carbazoles; Cell Cycle; Cell Proliferation; Colonic Neoplasms; DNA Topoisomerases, Type I; DNA, Neoplasm; Drug Resistance, Neoplasm; Flow Cytometry; Humans; Mutation, Missense; RNA, Messenger; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Topoisomerase I Inhibitors; Tumor Cells, Cultured
PubMed: 23836376
DOI: 10.3892/or.2013.2594