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Clinical Colorectal Cancer May 2005Edotecarin (PHA-782615; formerly J-107088) is a derivative of NB-506, an indolocarbazole antitumor agent. It is a novel inhibitor of topoisomerase I that induces... (Review)
Review
Edotecarin (PHA-782615; formerly J-107088) is a derivative of NB-506, an indolocarbazole antitumor agent. It is a novel inhibitor of topoisomerase I that induces single-strand DNA cleavage more effectively than NB-506 or camptothecin (CPT) and at different DNA sequences. The DNA-topoisomerase I complexes induced by edotecarin are more stable than those occurring after exposure to CPT or NB-506. The antitumor activity of edotecarin is less cell cycle dependent than other topoisomerase I inhibitors. Being an indolocarbazole, it is structurally related to staurosporine but does not possess protein kinase inhibitory properties. In addition, edotecarin does not form active metabolites and is not a substrate for in vitro P450-mediated metabolism. The antitumor activity of edotecarin has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in breast, cervix, pharynx, lung, prostate, colon, gastric, and hepatic cancer models. Edotecarin is effective on cells that have acquired resistance related to P-glycoprotein. In vitro synergy has been demonstrated when edotecarin was tested in combination with cisplatin, 5-fluorouracil, etoposide, paclitaxel, doxorubicin, vincristine, CPT, and gemcitabine. Three phase I and 5 phase II studies have been carried out to date. Combination studies of edotecarin with other chemotherapeutic agents are in current clinical trials. The primary dose-limiting toxicities were grade 3/4 neutropenia and febrile neutropenia. Dose-limiting diarrhea was observed only with a twice-weekly administration schedule. Recent progress in preclinical and clinical studies of edotecarin is reviewed.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Cell Cycle; Clinical Trials as Topic; Diarrhea; Drug Resistance, Neoplasm; Humans; Indoles; Neoplasms; Topoisomerase I Inhibitors
PubMed: 15929804
DOI: 10.3816/ccc.2005.n.014 -
IDrugs : the Investigational Drugs... Feb 2004Banyu Pharmaceutical Co Ltd and Pfizer Inc (formerly Pharmacia Corp) are developing edotecarin, an indolocarbazole topoisomerase I inhibitor, for the potential treatment...
Banyu Pharmaceutical Co Ltd and Pfizer Inc (formerly Pharmacia Corp) are developing edotecarin, an indolocarbazole topoisomerase I inhibitor, for the potential treatment of solid tumors.
Topics: Animals; Antineoplastic Agents; Carbazoles; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Enzyme Inhibitors; Humans; Indoles; Structure-Activity Relationship; Topoisomerase I Inhibitors
PubMed: 15057663
DOI: No ID Found -
Cancer Chemotherapy and Pharmacology Jul 2007Edotecarin (J-107088, formerly ED-749) is a potent indolocarbazole topoisomerase-I inhibitor that has the potential to treat solid tumors. The current studies evaluated...
PURPOSE
Edotecarin (J-107088, formerly ED-749) is a potent indolocarbazole topoisomerase-I inhibitor that has the potential to treat solid tumors. The current studies evaluated the potency and antitumor activity of edotecarin, as a single agent and in combination with capecitabine or docetaxel.
METHODS
Antiproliferative activity was tested in vitro in a panel of 13 mammary cell lines and antitumor efficacy was tested in vivo in various breast cancer models.
RESULTS
Edotecarin inhibited cellular proliferation in breast carcinoma cell lines: 50% inhibitory concentrations ranged from 8 nmol/L in SKBR-3 cells to approximately 30 micromol/L in BT20 cells. Single dose and weekly intravenous treatments with edotecarin 30 and 150 mg/kg produced significant antitumor activity in the SKBR-3 human breast carcinoma xenograft model, with no major toxicities, compared with vehicle solvent treatment. Daily administration of edotecarin 15 mg/kg for 10 days was not well tolerated, whereas the total dose of 150 mg/kg was safe when administered in a single injection. Edotecarin 3 and 30 mg/kg given after docetaxel in the nude mouse SKBR-3 xenograft model produced tumor growth delays that were greater than those observed with either agent alone and with no toxicity as evaluated on the basis of body weight reduction (<20%). Furthermore, edotecarin 3 mg/kg in combination with capecitabine produced more than additive effects and the combination was well tolerated. However, edotecarin at a dose of 30 mg/kg in combination with capecitabine was lethal. Edotecarin also exhibited potent antitumor activity against xenografted human MX-1 cells, MMTV-v-Ha-ras oncogene-driven mouse breast tumors, and chemically induced rat mammary tumors.
CONCLUSIONS
The data suggest that edotecarin may be useful as a single agent or a component of combination chemotherapy regimens for treating human breast cancer.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carbazoles; Cell Line, Tumor; Cell Proliferation; Docetaxel; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Humans; Indoles; Inhibitory Concentration 50; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Mice, Nude; Rats; Rats, Sprague-Dawley; Taxoids; Topoisomerase I Inhibitors
PubMed: 17089166
DOI: 10.1007/s00280-006-0365-8 -
Clinical Cancer Research : An Official... May 2006The novel indolocarbazole edotecarin (J-107088, formerly ED-749) differs from other topoisomerase I inhibitors both pharmacokinetically and pharmacodynamically. In...
The novel indolocarbazole edotecarin (J-107088, formerly ED-749) differs from other topoisomerase I inhibitors both pharmacokinetically and pharmacodynamically. In vitro, it is more potent than camptothecins and has a variable cytotoxic activity in 31 different human cancer cell lines. Edotecarin also possesses greater than additive inhibitory effects on cell proliferation when used in combination with other agents tested in vitro against various cancer cell lines. The present in vivo studies were done to extend the in vitro findings to characterize the antitumor effects of edotecarin when used either alone or in combination with other agents (i.e., 5-fluorouracil, irinotecan, cisplatin, oxaliplatin, and SU11248) in the HCT-116 human colon cancer xenograft model. Treatment effects were based on the delay in onset of an exponential growth of tumors in drug-treated versus vehicle control-treated groups. In all studies, edotecarin was active both as a single agent and in combination with other agents. Combination therapy resulted in greater than additive effects, the extent of which depended on the specific dosage regimen. Toxicity in these experiments was minimal. Of all 359 treated mice, the six that died of toxicity were in the high-dose edotecarin/oxaliplatin group. The results suggest that edotecarin may serve as effective chemotherapy of colon cancer when used as a single agent, in combination with standard regimens and other topoisomerase inhibitors or with novel agents, such as the multitargeted tyrosine kinase inhibitor SU11248.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Cell Division; Cell Line, Tumor; Colonic Neoplasms; Female; Humans; Indoles; Mice; Mice, Inbred BALB C; Mice, Nude; Topoisomerase I Inhibitors; Transplantation, Heterologous
PubMed: 16675581
DOI: 10.1158/1078-0432.CCR-05-1859 -
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 -
Cancer Chemotherapy and Pharmacology Jan 2007To assess the maximum tolerated dose, safety, and pharmacokinetic (PK) profile of escalating doses of the novel topoisomerase I (topo I) inhibitor edotecarin (J-107088)...
PURPOSE
To assess the maximum tolerated dose, safety, and pharmacokinetic (PK) profile of escalating doses of the novel topoisomerase I (topo I) inhibitor edotecarin (J-107088) given as a 2-h intravenous (IV) infusion once every 21 days in patients with advanced solid tumors who had not responded to standard therapy.
PATIENTS AND METHODS
Twenty-nine patients (18M:11F) received a 2-h IV infusion of edotecarin in doses of 6, 8, 11, 13, or 15 mg/m(2) every 21 days (with an additional 1-2 weeks permitted for recovery) and were evaluated for safety, PK, and tumor response.
RESULTS
The most common non-hematologic toxicities were grade 1-2 nausea, fatigue, anorexia, vomiting, and fever. The most common hematologic toxicities were grade 1-2 thrombocytopenia and grade 3-4 neutropenia, leukopenia, and anemia. No grade 3-4 diarrhea was reported. Dose-limiting toxicities were observed in four patients at the 15 mg/m(2) dose and one patient at the 13 mg/m(2) dose. These toxicities included grade 3 nausea, vomiting, headache, and fatigue, as well as grade 4 neutropenia and febrile neutropenia. The maximum tolerated dose was declared at 15 mg/m(2). One patient with bladder cancer had a confirmed partial response at a dose of 13 mg/m(2). There was a trend to dose-proportional increases in edotecarin peak plasma concentrations and area under the curve values. Renal excretion of edotecarin was minimal (3-8% of the dose).
CONCLUSION
The recommended Phase II dose of edotecarin is 13 mg/m(2) once every 21 days. The toxicities in this study were those typical of cytotoxic chemotherapy and less severe than those associated with other topo I inhibitors. The observed safety profile and preliminary evidence of clinical benefit warrant further investigation of this drug as monotherapy or part of combination therapy in patients with solid tumors.
Topics: Adult; Aged; Aged, 80 and over; Area Under Curve; Blood Cell Count; Carbazoles; Chromatography, High Pressure Liquid; Cohort Studies; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fatigue; Female; Fever; Hematologic Diseases; Humans; Indoles; Infusions, Intravenous; Male; Middle Aged; Nausea; Neoplasms; Neutropenia; Topoisomerase I Inhibitors; Vomiting
PubMed: 16819636
DOI: 10.1007/s00280-006-0267-9 -
Cancer Chemotherapy and Pharmacology Aug 2006Edotecarin (J-107088) is a potent indolocarbazole topoisomerase I inhibitor which is structurally distinct from the camptothecins. This study aimed to determine the...
PURPOSE
Edotecarin (J-107088) is a potent indolocarbazole topoisomerase I inhibitor which is structurally distinct from the camptothecins. This study aimed to determine the maximum tolerated dose (MTD), the recommended dose for future Phase II studies and the safety, pharmacokinetic profile, and preliminary antitumor activity of edotecarin in a population of patients with advanced solid tumors.
EXPERIMENTAL DESIGN
Edotecarin was administered as a single dose by IV infusion over 2 h every 21 days (with 1 week permitted for recovery from toxicities, if needed) in patients with advanced solid tumors. Doses ranged from 8 to 15 mg/m(2). Pharmacokinetic assessments were performed during and after the first administration.
RESULTS
Twenty-four patients received 61 cycles of therapy. Dose-limiting toxicities (infection, febrile neutropenia, constipation, ileus, and prolonged grade 4 granulocytopenia) were observed in 3 of 5 evaluable patients at the 15 mg/m(2) dose, defining the MTD. The most commonly reported non-hematologic toxicities were anorexia, nausea, malaise, and constipation. Diarrhea was neither frequent nor severe. Neutropenia was the most common hematologic toxicity (grade 3-4 in 21/23 patients during cycle 1). Plasma concentrations of edotecarin rose rapidly following the start of the 2-hour infusion, reaching C (max) values of 103+/-17 ng/ml at the 13 mg/m(2) dose, and decreased steeply after the end of the infusion. Plasma concentrations declined to approximately 1-2 ng/ml at 26 h post start of infusion, the last PK sampling time point. The mean apparent plasma half-life of the drug was 20 h, which should be considered a preliminary estimate until results from studies with a longer duration of plasma sampling are available. A mean of 1.4-3.6% of the dose was recovered as unchanged drug in the urine over 48 h. Unconfirmed tumor regression > or =50% was observed in 2 patients, 1 with metastatic gastric carcinoma and 1 with esophageal cancer.
CONCLUSIONS
The MTD of edotecarin administered IV over 2 h every 21 days was 15 mg/m(2). The recommended dose for Phase II studies with a 3-week schedule (with 1 week permitted for recovery from toxicities, if needed) is 13 mg/m(2). The observed safety profile and preliminary evidence of antitumor activity warrant further investigation of this drug in solid tumors.
Topics: Adult; Aged; Antineoplastic Agents; Carbazoles; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Inhibitors; Female; Humans; Indoles; Male; Middle Aged; Topoisomerase I Inhibitors
PubMed: 16308697
DOI: 10.1007/s00280-005-0149-6 -
Journal of Medicinal Chemistry May 2009The replacement of 1,3-dihydroxy-2-propylamino moiety at the N6-position of edotecarin (1) by arylmethylamino groups yielded a number of more potent topoisomerase I...
The replacement of 1,3-dihydroxy-2-propylamino moiety at the N6-position of edotecarin (1) by arylmethylamino groups yielded a number of more potent topoisomerase I inhibitors with better cytotoxic (CTX) activities in vitro than edotecarin. Among them, the three most potent pyridylmethyl analogues, compounds 22g, 22m, and 23c, showed better antitumor activities against MKN-45 human stomach cancer or MX-1 human breast cancer xenografted mice than those of edotecarin. Furthermore, compounds 22m and 23c exhibited complete response against MX-1 cells implanted in mice.
Topics: Amines; Animals; Antineoplastic Agents; Breast Neoplasms; Carbazoles; Cell Line, Tumor; Enzyme Inhibitors; Female; Humans; Hydrocarbons, Aromatic; Mice; Pyridines; Stomach Neoplasms; Structure-Activity Relationship; Topoisomerase I Inhibitors; Xenograft Model Antitumor Assays
PubMed: 19397324
DOI: 10.1021/jm801641t -
Biochemical Pharmacology Mar 2008Topoisomerase I (TopoI), an essential enzyme, produces a DNA single strand break allowing DNA relaxation for replication. The enzymatic mechanism involves sequential... (Review)
Review
Topoisomerase I (TopoI), an essential enzyme, produces a DNA single strand break allowing DNA relaxation for replication. The enzymatic mechanism involves sequential transesterifcations. The breakage and closure reactions generate phosphodiester bonds and similar free energies, so the reaction is freely reversible. The TopoI reaction intermediate consists of enzyme covalently linked to DNA dubbed a 'cleavable complex'. Covalently bound TopoI-DNA complexes can be recovered. Camptothecin analogs, topotecan and irinotecan, are approved TopoI-targeted drugs. Both have limitations due to the equilibrium between the camptothecin lactone and ring-opened forms. Several strategies are being explored to develop improved TopoI inhibitors. Homocamptothecins, in which the metabolically labile camptothecin lactone is replaced with a more stable seven-membered beta-hydroxylactone, are potent anticancer agents. Gimatecan is a seven-position modified lipophilic camptothecin developed to provide rapid uptake and accumulation in cells and a stable TopoI-DNA-drug ternary complex. Diflomotecan, a homocamptothecin, and gimatecan are in Phase II clinical trial. Among non-camptothecins, edotecarin, an indolocarbazole that results in DNA C/T-G cleavage compared with T-G/A for camptothecins, is in Phase II clinical trial. Indenoisoquinolines were identified as TopoI inhibitors by the NCI 60-cell line COMPARE analysis. Co-crystal structures of two indenoisoquinolines with TopoI-DNA elucidated the structure of the ternary complex. Indenoisoquinolines are in preclinical development. Dibenzonaphthyridinone TopoI inhibitors have undergone extensive structure-activity examination. ARC-111 was selected for in-depth preclinical study. Biomarkers are under investigation to predict clinical efficacy from preclinical models, to allow determination of drug targeting in vivo and to aid selection of patients most likely to benefit from TopoI inhibitor therapy. gamma-H2AX formation may be a useful pharmacodynamic marker. A gene signature developed for topotecan sensitivity/resistance may have value in patient identification. Convergence of these efforts should result in clinically effective second generation TopoI inhibitors.
Topics: Animals; Antineoplastic Agents; Biomarkers; Camptothecin; Carbazoles; Humans; Indenes; Indoles; Isoquinolines; Naphthyridines; Topoisomerase I Inhibitors
PubMed: 18061144
DOI: 10.1016/j.bcp.2007.10.016 -
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