Pharmacokinetics and metabolism of O-(chloroacetyl-carbamoyl) fumagillol (TNP-470, AGM-1470) in rhesus monkeys.


:The metabolic disposition and pharmacokinetics of TNP-470 were investigated in rhesus monkeys following intravenous administration of 5 mg/kg of [3H]-TNP-470. Rapid and extensive metabolism of parent drug to six metabolites occurred as demonstrated by the absence of unchanged drug in plasma and urine at time points as early as 6 min after administration. Substantial, yet variable, plasma levels of M-IV were detected in all three monkeys with a mean Cmax value of 3.54 microM. Five other metabolites, labeled M-I, M-II, M-III, M-V and M-VI, were also detected in biological fluids of monkeys. M-II, M-V and M-VI exhibited similar kinetic profiles with apparent plasma elimination half-life values of 0.91 +/- 0.37, 2.42 +/- 0.13 and 1.19 +/- 0.29 h respectively. In contrast, M-I, M-III and M-IV exhibited much shorter apparent plasma half-life values of 30 min or less. Urinary recovery within 36 h represented only 19.90 +/- 6.09% of the total administered dose. No radioactivity was detected beyond 36 h and during a 15-day sample collection period, suggesting that nonrenal (biliary) elimination of TNP-470 metabolites is a predominant excretion route in nonhuman primates. This study provides the first detailed in vivo analysis of TNP-470 metabolism and disposition using an animal model highly predictive of humans, consistent with the detection of the same TNP-470 metabolites in human tissues. A detailed understanding of TNP-470 metabolism and disposition is critical to fully elucidate the pharmacodynamic properties of this new anticancer drug as clinical investigations proceed.


Cretton-Scott E,Placidi L,McClure H,Anderson DC,Sommadossi JP




Has Abstract


1996-01-01 00:00:00












  • Comparison of the efficacy of tropisetron versus a metoclopramide cocktail based on the intensity of cisplatin-induced emesis.

    abstract::Cisplatin-induced emesis is one of the most feared side effects in cancer treatment. High-dose metoclopramide may prevent only 30-40% of cases of acute emesis. Investigations to test the efficacy of new antiemetics are mandatory. We compared the efficacy, toxicity, and patients' preference for tropisetron, a new 5-hyd...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Chang TC,Hsieh F,Lai CH,Tseng CJ,Cheng HH,Li CL,Michael BJ,Soong YK

    更新日期:1996-01-01 00:00:00

  • Combination chemotherapy for advanced urothelial-tract carcinoma.

    abstract::Between December 1982 and November 1990, 31 patients with advanced urothelial carcinoma were treated with one of two combination chemotherapy regimens. A total of 20 patients were treated with 3 mg/m2 mitomycin C and 300 mg/m2 cyclophosphamide given intravenously every 10-14 days and with 180 mg/m2 5-fluorouracil (5-F...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 临床试验,杂志文章


    authors: Sahashi M,Ono Y,Matsuura O,Ohshima S,Fukushima M

    更新日期:1992-01-01 00:00:00

  • A first in human study of SB-743921, a kinesin spindle protein inhibitor, to determine pharmacokinetics, biologic effects and establish a recommended phase II dose.

    abstract:PURPOSE:To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics, and pharmacodynamics of SB-743921 when administered as a 1-h infusion every 21 days to patients with advanced solid tumors or relapsed/refractory lymphoma. METHODS:Patients who failed prior standard therapy o...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: Holen KD,Belani CP,Wilding G,Ramalingam S,Volkman JL,Ramanathan RK,Vasist LS,Bowen CJ,Hodge JP,Dar MM,Ho PT

    更新日期:2011-02-01 00:00:00

  • Incorporation of OSI-7836 into DNA of Calu-6 and H460 xenograft tumors.

    abstract::OSI-7836 (4'-thio-beta-D-arabinofuranosylcytosine) is a novel nucleoside analog in phase I clinical development for the treatment of cancer. As with other nucleoside analogs, the proposed mechanism of action involves phosphorylation to the triphosphate form followed by incorporation into cellular DNA, leading to cell ...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: Richardson F,Black C,Richardson K,Franks A,Wells E,Karimi S,Sennello G,Hart K,Meyer D,Emerson D,Brown E,LeRay J,Nilsson C,Tomkinson B,Bendele R

    更新日期:2005-03-01 00:00:00

  • IPI-504, a novel and soluble HSP-90 inhibitor, blocks the unfolded protein response in multiple myeloma cells.

    abstract:BACKGROUND:Inhibitors of heat shock protein (Hsp) 90 induce apoptosis in multiple myeloma (MM) cells, but the molecular mechanisms underlying this cytotoxic outcome are not clear. Here, we investigate the effect of IPI-504, a novel and highly soluble inhibitor of the Hsp90 ATPase activity, on the unfolded protein respo...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: Patterson J,Palombella VJ,Fritz C,Normant E

    更新日期:2008-05-01 00:00:00

  • Inhibition of growth factor binding, Ca2+ signaling and cell growth by polysulfonated azo dyes related to the antitumor agent suramin.

    abstract::The ability of the polysulfonated antitumor drug suramin and six related polysulfonated azo dyes to inhibit the cell growth, platelet-derived growth factor (PDGF)-receptor binding, and intracellular Ca2+ signaling of Swiss 3T3 fibroblasts was studied. Some of the azo dyes were more potent inhibitors of PDGF binding th...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: Powis G,Seewald MJ,Melder D,Hoke M,Gratas C,Christensen TA,Chapman DE

    更新日期:1992-01-01 00:00:00

  • Adjuvant intra-arterial 5-fluoruracil, leucovorin, epirubicin and carboplatin with or without systemic gemcitabine after curative resection for pancreatic adenocarcinoma.

    abstract:BACKGROUND:The role of adjuvant therapy in pancreatic cancer remains controversial. Gemcitabine given systemically seems to be effective; intra-arterial chemotherapy (IAC) has a deep rationale. PATIENTS AND METHODS:The goal was to evaluate the impact of postoperative IAC followed or not by systemic gemcitabine in pati...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 临床试验,杂志文章,多中心研究


    authors: Cantore M,Serio G,Pederzoli P,Mambrini A,Iacono C,Pulica C,Capelli P,Lombardi M,Torri T,Pacetti P,Pagani M,Fiorentini G

    更新日期:2006-10-01 00:00:00

  • Tumor inhibition by titanocene complexes: influence on xenografted human adenocarcinomas of the gastrointestinal tract.

    abstract::The present study deals with the influence of some bis(eta 5-cyclopentadienyl)titanium(IV) (titanocene) complexes, mainly represented by titanocene dichloride, on the development of several human gastrointestinal (GI) carcinomas (one stomach, seven colon, four sigmoid, and two rectal adenocarcinomas), all xenografted ...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: Köpf-Maier P

    更新日期:1989-01-01 00:00:00

  • Antihelicase action of CI-958, a new drug for prostate cancer.

    abstract::CI-958, a new DNA-intercalating drug derived from a series of substituted 2H-[1] benzothiopyrano[4,3,2-cd]indazoles, is being tested in clinical trails because of its curative properties against murine solid tumor models and because it has demonstrated activity in a pilot phase II study of patients with hormone-refrac...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: Lun L,Sun PM,Trubey CM,Bachur NR

    更新日期:1998-01-01 00:00:00

  • Flavone acetic acid distribution in human malignant tumors.

    abstract::The pharmacokinetics of flavone acetic acid (FAA) after a dose of 4.8 mg/m2 given i.v. over 1 h was investigated in 13 patients with different solid tumors. The mean volume of distribution and clearance were 52 +/- 4 l/m2 and 2.6 +/- 0.2 l/h x m2, respectively. A tumor or metastasis biopsy was obtained from six patien...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: Damia G,Freschi A,Sorio R,Braida A,Caruso G,Quaia M,Monfardini S,D'Incalci M

    更新日期:1990-01-01 00:00:00

  • Pharmacokinetic analysis and antitumor efficacy of MKT-077, a novel antitumor agent.

    abstract::MKT-077 (1-ethyl-2-[[3-ethyl-5-(3-methylbenzothiazolin-2-yliden)]-4- oxothiazolidin-2-ylidenemethyl] pyridinium chloride), a novel rhodacyanine dye in phase I/II clinical trials, may provide a new approach to cancer therapy based on the accumulation in the mitochondria of the cells of certain carcinomas, for example, ...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: Tatsuta N,Suzuki N,Mochizuki T,Koya K,Kawakami M,Shishido T,Motoji N,Kuroiwa H,Shigematsu A,Chen LB

    更新日期:1999-01-01 00:00:00

  • Wortmannin inhibits the growth of mammary tumors despite the existence of a novel wortmannin-insensitive phosphatidylinositol-3-kinase.

    abstract:PURPOSE:Phosphatidylinositol (PtdIns) 3-kinase is an important mediator of many cellular functions. The study of PtdIns 3-kinase has been facilitated by the existence of the potent irreversible inhibitor of p110 PtdIns 3-kinase, wortmannin. The purpose of the study was to investigate the relationship between the cell g...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: Lemke LE,Paine-Murrieta GD,Taylor CW,Powis G

    更新日期:1999-01-01 00:00:00

  • Utilization of the HTSCA and CFU-C assay to identify two new 2-chloroethylnitrosourea congeners of amino acid amides with increased in vitro activity against human glioma compared with BCNU.

    abstract::AspCNU and SarCNU are two amino acid amide congeners (L-asparaginamide and sarcosinamide congeners) of chloroethylnitrosoureas. The in vitro myelotoxicity of these agents compared with BCNU at 1-8 micrograms/ml was determined in bone marrow cells from normal volunteers in the CFU-C assay. AspCNU and SarCNU were signif...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: Panasci LC,Dufour M,Chevalier L,Isabel G,Lazarus P,McQuillan A,Arbit E,Brem S,Feindel W

    更新日期:1985-01-01 00:00:00

  • An apparent clinical pharmacokinetic drug-drug interaction between bevacizumab and the anti-placental growth factor monoclonal antibody RO5323441 via a target-trapping mechanism.

    abstract:PURPOSE:RO5323441 is a humanized anti-placental growth factor (PlGF) monoclonal antibody that has shown preclinical activity in several cancer models. The objective of this analysis is to examine the pharmacokinetic (PK) results from four Phase I studies that have been conducted with RO5323441 (n = 61) and to report an...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章,多中心研究


    authors: Wang K,Stark FS,Schlothauer T,Lahr A,Cosson V,Zhi J,Habben K,Tessier J,Schick E,Staack RF,Krieter O

    更新日期:2017-04-01 00:00:00

  • Association of UGT2B7 and ABCB1 genotypes with morphine-induced adverse drug reactions in Japanese patients with cancer.

    abstract:PURPOSE:To investigate the effects of genetic polymorphisms on morphine-induced adverse events in cancer patients. METHODS:We examined the relation of morphine-related adverse events to polymorphisms in UDP-glucuronosyltransferase (UGT) 2B7, ATP-binding cassette, sub-family B, number 1 (ABCB1), and μ-opioid receptor 1...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: Fujita K,Ando Y,Yamamoto W,Miya T,Endo H,Sunakawa Y,Araki K,Kodama K,Nagashima F,Ichikawa W,Narabayashi M,Akiyama Y,Kawara K,Shiomi M,Ogata H,Iwasa H,Okazaki Y,Hirose T,Sasaki Y

    更新日期:2010-01-01 00:00:00

  • Gemcitabine activity in cervical cancer cell lines.

    abstract:PURPOSE:Gemcitabine (2',2'-difluorodeoxycytidine) is an antineoplastic agent with activity against a variety of solid tumors. To investigate its in vitro activity toward cervical cancer, we exposed six cervical cancer cell lines to gemcitabine. METHODS:Combinational cytotoxic studies using viability tests and clonogen...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: Hernández P,Olivera P,Dueñas-Gonzalez A,Pérez-Pastenes MA,Zárate A,Maldonado V,Meléndez-Zajgla J

    更新日期:2001-12-01 00:00:00

  • Phase I study of veliparib in combination with gemcitabine.

    abstract:BACKGROUND:Veliparib (ABT-888) is an oral PARP inhibitor expected to increase gemcitabine activity. This phase I determined the maximal tolerable dose (MTD), dose-limiting toxicities (DLT), antitumor activity, pharmacokinetics (PK), and pharmacodynamics (PD) of veliparib combined with gemcitabine. METHODS:Patients wit...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章,多中心研究


    authors: Stoller R,Schmitz JC,Ding F,Puhalla S,Belani CP,Appleman L,Lin Y,Jiang Y,Almokadem S,Petro D,Holleran J,Kiesel BF,Ken Czambel R,Carneiro BA,Kontopodis E,Hershberger PA,Rachid M,Chen A,Chu E,Beumer JH

    更新日期:2017-09-01 00:00:00

  • Analysis of gastric cancer with cDNA microarray.

    abstract::Recent advances in cDNA microarray techniques have enabled us to study the expression of many genes simultaneously. As gastric cancer remains one of the most common cancers in Japan, we studied gene expression profiles in gastric cancer by cDNA microarray analysis to determine if it would be clinically useful. We demo...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: Haraguchi N,Inoue H,Mimori K,Tanaka F,Utsunomiya T,Yoshikawa K,Mori M

    更新日期:2004-09-01 00:00:00

  • Detection of adriamycin-induced cardiotoxicity in cultured heart cells with technetium 99m-SESTAMIBI.

    abstract::Adriamycin, a broad-spectrum cytotoxic agent useful in cancer chemotherapy, is limited by a dose-dependent cardiomyopathy mediated in part by disruption of mitochondrial energetics. Hexakis(2-methoxyisobutyl isonitrile)technetium(I) (99mTc-SESTAMIBI) is a gamma-emitting radiopharmaceutical with myocellular accumulatio...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: Piwnica-Worms D,Chiu ML,Kronauge JF

    更新日期:1993-01-01 00:00:00

  • Pegylated liposomal doxorubicin, 5-fluorouracil and cisplatin versus mitomycin-C, 5-fluorouracil and cisplatin for advanced gastric cancer: a randomized phase II trial.

    abstract:PURPOSE:Clinical data suggested that a regimen incorporating doxorubicin to 5-fluorouracil (5-FU) and cisplatin may be more effective but probably quite toxic for advanced gastric cancer patients. With the aim to maintain efficacy while reducing toxicity, we compared the activity and safety of a combination of 5-FU, ci...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章,多中心研究,随机对照试验


    authors: Cascinu S,Galizia E,Labianca R,Ferraù F,Pucci F,Silva RR,Luppi G,Beretta GD,Berardi R,Scartozzi M

    更新日期:2011-07-01 00:00:00

  • A new liposomal formulation of Gemcitabine is active in an orthotopic mouse model of pancreatic cancer accessible to bioluminescence imaging.

    abstract::Despite its rapid enzymatic inactivation and therefore limited activity in vivo, Gemcitabine is the standard drug for pancreatic cancer treatment. To protect the drug, and achieve passive tumor targeting, we developed a liposomal formulation of Gemcitabine, GemLip (Ø: 36 nm: 47% entrapment). Its anti-tumoral activity ...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: Bornmann C,Graeser R,Esser N,Ziroli V,Jantscheff P,Keck T,Unger C,Hopt UT,Adam U,Schaechtele C,Massing U,von Dobschuetz E

    更新日期:2008-03-01 00:00:00

  • Inhibition of human breast cancer colony formation by anticalmodulin agents: trifluoperazine, W-7, and W-13.

    abstract::The effects of anticalmodulin agents, namely trifluoperazine (TFP) and two naphthalene sulfonamide derivatives (W-7 and W-13), were tested on the growth of a human breast cancer cell line (MDA-MB-231) using a soft agar clonogenic assay. The results of this in vitro study reveal that TFP, W-7, and W-13 had the ability ...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: Wei JW,Hickie RA,Klaassen DJ

    更新日期:1983-01-01 00:00:00

  • Cytochrome P450 isozymes 3A4 and 2B6 are involved in the in vitro human metabolism of thiotepa to TEPA.

    abstract:PURPOSE:To establish the cytochrome P450 (CYP) isozymes involved in the metabolism of the alkylating agent, thiotepa, to the pharmacologically active metabolite, TEPA. METHODS:In vitro chemical inhibition studies were conducted by incubating thiotepa and pooled human hepatic microsomes in the presence of known inhibit...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: Jacobson PA,Green K,Birnbaum A,Remmel RP

    更新日期:2002-06-01 00:00:00

  • Phase I study of non-pegylated liposomal doxorubicin in children with recurrent/refractory high-grade glioma.

    abstract:PURPOSE:To determine the maximum recommended dose (RD) and pharmacokinetics of Myocet®, a non-pegylated liposomal doxorubicin, in children. METHODS:Eligible patients were children with refractory high-grade glioma who had received prior chemotherapy and radiotherapy but no anthracyclines. Cohorts of at least three pat...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: Chastagner P,Devictor B,Geoerger B,Aerts I,Leblond P,Frappaz D,Gentet JC,Bracard S,André N

    更新日期:2015-08-01 00:00:00

  • A reliable method to determine which candidate chemotherapeutic drugs effectively inhibit tumor growth in patient-derived xenografts (PDX) in single mouse trials.

    abstract:PURPOSE:We report on a statistical method for grouping anti-cancer drugs (GRAD) in single mouse trials (SMT). The method assigns candidate drugs into groups that inhibit or do not inhibit tumor growth in patient-derived xenografts (PDX). It determines the statistical significance of the group assignments without replic...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: Gordon D,Axelrod DE

    更新日期:2019-12-01 00:00:00

  • Pharmacokinetics of lenalidomide during high cut-off dialysis in a patient with multiple myeloma and renal failure.

    abstract:INTRODUCTION:High cut-off dialysis, increasingly used in multiple myeloma patients, is susceptible to influence anticancer drug elimination. We report about lenalidomide disposition in a patient on high cut-off dialysis for renal failure secondary to myeloma cast nephropathy. METHODS:The patient received a higher dosa...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: Dao K,Lu Y,Peer CJ,Figg WD,Stadelmann R,Burnier M,Buclin T,Kissling S

    更新日期:2017-01-01 00:00:00

  • Cystatin C as a predictor factor in patients with renal cell carcinoma treated by everolimus.

    abstract:BACKGROUND:We evaluated the influence of serum cystatin C (CysC) with respect to other glomerular filtration rate (GFR) markers on the treatment effect of everolimus in a phase II study in patients with metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS:Outcomes were from the study's primary analysis. GFR w...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: Bodnar L,Stec R,Dzierżanowska M,Synowiec A,Cierniak S,Kade G,Szczylik C

    更新日期:2016-08-01 00:00:00

  • Wide variation in tissue, systemic, and drain fluid exposure after oxaliplatin-based HIPEC: results of the GUTOX study.

    abstract:PURPOSE:In this exploratory study, the effect of postprocedural flushing with crystalloids after oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) on platinum concentrations in peritoneal tissue, blood, and drain fluid was studied. Interpatient variability in oxaliplatin pharmacokinetics and the relat...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: de Jong LAW,Elekonawo FMK,Lambert M,de Gooyer JM,Verheul HMW,Burger DM,de Wilt JHW,Chatelut E,Ter Heine R,de Reuver PR,Bremers AJA,van Erp NP

    更新日期:2020-07-01 00:00:00

  • Effect of age on the pharmacokinetics of busulfan in patients undergoing hematopoietic cell transplantation; an alliance study (CALGB 10503, 19808, and 100103).

    abstract:PURPOSE:Older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome have often been excluded from myeloablative-conditioning regimens containing busulfan because of non-disease-related morbidity and mortality. We hypothesized that busulfan clearance (BuCL) in older patients (>60 years) would be reduce...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 临床试验,杂志文章


    authors: Beumer JH,Owzar K,Lewis LD,Jiang C,Holleran JL,Christner SM,Blum W,Devine S,Kolitz JE,Linker C,Vij R,Alyea EP,Larson RA,Ratain MJ,Egorin MJ

    更新日期:2014-11-01 00:00:00

  • In vitro phase II comparison of the cytotoxicity of a novel platinum analog, nedaplatin (254-S), with that of cisplatin and carboplatin against fresh, human ovarian cancers.

    abstract:PURPOSE:To compare the in vitro cytotoxicity of nedaplatin, an investigational platinum analog, with that of the standard platinum agents, cisplatin and carboplatin, against fresh human, epithelial ovarian cancers. METHODS:The Hamburger-Salmon human tumor colony-forming assay (HTCA) was used to measure the chemosensit...

    journal_title:Cancer chemotherapy and pharmacology

    pub_type: 杂志文章


    authors: Alberts DS,Fanta PT,Running KL,Adair LP Jr,Garcia DJ,Liu-Stevens R,Salmon SE

    更新日期:1997-01-01 00:00:00