Antitumor Agents (antitumor + agent)

Distribution by Scientific Domains
Distribution within Chemistry

Kinds of Antitumor Agents

  • potent antitumor agent
  • potential antitumor agent


  • Selected Abstracts


    Characterization of the Interaction of TZT-1027, a Potent Antitumor Agent, with Tubulin

    CANCER SCIENCE, Issue 7 2000
    Tsugitaka Natsume
    TZT-1027, a derivative of dolastatin 10 isolated from the Indian Ocean sea hare Dolabella auricularia in 1987 by Pettit et al., is a potent antimicrotubule agent. We have compared the activity of TZT-1027 with that of dolastatin 10 as well as the vinca alkaloids vinblastine (VLB), vincristine (VCR) and vindesine (VDS). TZT-1027 and dolastatin 10 inhibited microtubule polymerization concentration-dependently at 1,100 ,M with IC50 values of 2.2±0.6 and 2.3±0.7 ,M, respectively. VLB, VCR and VDS inhibited microtubule polymerization at 1,3 ,M with IC50 values of 2.7±0.6, 1.6±0.4 and 1.6±0.2 ,M, respectively, but showed a slight decrease in inhibitory effect at concentrations of 10 ,M or more. TZT-1027 also inhibited monosodium glutamate-induced tubulin polymerization concentration-dependently at 0.3,10 ,M, with an IC50 of 1.2 ,M, whereas VLB was only effective at 0.3,3 ,M, with an IC50 of 0.6 ,M, and caused so-called "aggregation" of tubulin at 10 ,M. Scatchard analysis of the binding data for [3H]VLB suggested one binding site (Kd 0.2±0.04 ,M and Bmax 6.0±0.26 nM/mg protein), while that for [3H]TZT-1027 suggested two binding sites, one of high affinity (Kd 0.2±0.01 ,M and Bmax 1.7±0.012 nM/mg protein) and the other of low affinity (Kd 10.3±1.46 ,M, and Bmax 11.6±0.83 nM/mg protein). [3H]TZT-1027 was completely displaced by dolastatin 10 but only incompletely by VLB. [3H]VLB was completely displaced by dolastatin 10 and TZT-1027. Furthermore, TZT-1027 prevented [3H]VLB from binding to tubulin in a non-competitive manner according to Lineweaver-Burk analysis. TZT-1027 concentrationdependently inhibited both [3H]guanosine 5,-triphosphate (GTP) binding to and GTP hydrolysis on tubulin. VLB inhibited the hydrolysis of GTP on tubulin concentration-dependently to a lesser extent than TZT-1027, but no inhibitory effect of VLB on [3H]GTP binding to tubulin was evident even at 100 ,M. Thus, TZT-1027 affected the binding of VLB to tubulin, but its binding site was not completely identical to that of VLB. TZT-1027 had a potent inhibitory effect on tubulin polymerization and differed from vinca alkaloids in its mode of action against tubulin polymerization. [source]


    ChemInform Abstract: 2-[N1 -2-Pyrimidyl-aminobenzenesulfonamido] Ethyl 4-Bis(2-chloroethyl) Aminophenyl Butyrate: A Potent Antitumor Agent.

    CHEMINFORM, Issue 32 2001
    Zhaohua Huang
    Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source]


    Total Synthesis of Potent Antitumor Agent (,)-Lasonolide,A: A Cycloaddition-Based Strategy

    CHEMISTRY - AN ASIAN JOURNAL, Issue 10 2008

    Abstract A detailed account of the enantioselective total synthesis of (,)-lasonolide,A is described. Our initial synthetic route to the top tetrahydropyran ring involved Evans asymmetric alkylation as the key step. Initially, we relied on the diastereoselective alkylation of an ,-alkoxyacetimide derivative containing an ,, stereogenic center and investigated such an asymmetric alkylation reaction. Although alkylation proceeded in good yield, the lack of diastereoselectivity prompted us to explore alternative routes. Our subsequent successful synthetic strategies involved highly diastereoselective cycloaddition routes to both tetrahydropyran rings of lasonolide,A. The top tetrahydropyran ring was constructed stereoselectively by an intramolecular 1,3-dipolar cycloaddition reaction. The overall process constructed a bicyclic isoxazoline, which was later unravelled to a functionalized tetrahydropyran ring as well as a quaternary stereocenter present in the molecule. The lower tetrahydropyran ring was assembled by a Jacobsen catalytic asymmetric hetero-Diels,Alder reaction as the key step. The synthesis also features a Lewis acid catalyzed epoxide opening to form a substituted ether stereoselectively. [source]


    Synthesis of Polyamines from Ethylenediamine and Their Platinum(II) Complexes, Potential Antitumor Agents

    EUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 9 2006
    Mara Rubia Costa Couri
    Abstract This work describes the synthesis and characterization of five new amine ligands and also the preparation and characterization of their respective platinum(II) complexes by reaction with K2PtCl4 in water. These ligands were obtained by treatment of different halides or epoxides with ethylenediamine. Cytotoxic activity and cellular accumulation of three complexes were investigated in a human small-cell lung carcinoma cell line and its cisplatin resistant subline. The introduction of a spacer (cycle) between the two platinum atoms leads to a significant decrease in cytotoxic activity. At equitoxic doses, the intracellular platinum concentrations found for compounds 12 and 15 were significantly higher than those found for the reference compounds, cisplatin, carboplatin, or compound 9. This fact suggests that the formation of adducts between compounds 12 and 15 and the putative pharmacological target, DNA, is less favored. If these compounds bind more slowly to DNA, interaction with other intracellular ligands such as sulfur-containing molecules will become relevant and it may be the reason for the elevated intracellular platinum concentrations. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006) [source]


    Ab Initio Structure/Reactivity Investigations of Illudin-Based Antitumor Agents: A Model for Reaction in vivo

    HELVETICA CHIMICA ACTA, Issue 12 2003
    Laura
    (Hydroxymethyl)acylfulvene (HMAF, irofulven; 4), a third-generation derivative of a natural product extracted from the mushroom Omphalotus illudens, is selectively toxic towards certain forms of malignant tumors. Conversion of HMAF and cognates to stable aromatic derivatives is triggered by thiol attack in vitro and in vivo. Quantum-chemical methods predict well the structure for several functionalized derivatives of irofulven as compared to known X-ray crystallographic structures. Computational reaction profiles for thiol attack and aromatic rearrangement of irofulven and illudin S, a toxin from which irofulven is derived, provide insight into HMAF's selectivity and toxicity. Methods used include hybrid density-functional theory (HDFT), HartreeFock (HF), and MøllerPlesset second-order perturbation theory (MP2). Solvent effects have been explored by means of the new continuum-solvation method, COSab, presented in an accompanying paper. [source]


    Synthesis and Structure-Activity Relationship Studies of Pyrazole-based Heterocycles as Antitumor Agents

    ARCHIV DER PHARMAZIE, Issue 7 2010
    Ahmad M. Farag
    Abstract Several 4-cyano-1,5-diphenylpyrazoles attached to different heterocyclic ring systems at position 3 were synthesized starting from ethyl 4-cyano-1,5-diphenyl-1H -pyrazole-3-carboxylate 1. The newly synthesized compounds were tested in vivo for their anti-estrogenic effects and evaluated in vitro for their cytotoxic properties against estrogen-dependent tumors. 3-(5-Mercapto-1,3,4-oxadiazole-2-yl)-1,5-diphenyl-1H -pyrazole-4-carbonitrile 13 revealed the highest cytotoxic activity with a GI50 value equal to 40 nM against the IGROVI ovarian tumor cell line. It also showed an anti-estrogen activity 1.6 more effective than the reference drug, in addition to a high tolerable dose. 3-(5-(Methylthio)-4-phenyl-4H -1,2,4-triazol-3-yl)-1,5-diphenyl-1H -pyrazole-4-carbonitrile 7 was found to have the highest anti-estrogenic activity, while 1,5-diphenyl-3-[5-(phenylamino)-1,3,4-thiadiazol-2-yl]-1H -pyrazole-4-carbonitrile 11 showed the lowest activity. The oral LD50 values revealed that most of the tested compounds are relatively nontoxic. [source]


    Platinum and Palladium-triazole Complexes as Highly Potential Antitumor Agents

    ARCHIV DER PHARMAZIE, Issue 4 2010
    Najim A. Al-Masoudi
    Abstract The palladium complexes [(dppe)Pd(L)2PdCl2], [(dppe)Pd(L)2PtCl2], [(dppp)Pd(L)2PdCl2], [(dppm) Pd(L)2NiCl2], and [(dppm)Pd(L)2SnCl4] 15,19 were prepared. The antiproliferative activity of the newly synthesized complexes as well as their previously prepared analogues 3,14 and 20,26 were screened against a large panel of human cancer cell lines derived from haematological CD4+ human T-cells containing an integrated HTLV-1 genome (MT-4). The complex 12a, b exhibited remarkable antiproliferative activity against MT-4, CD4+ human acute T-lymphoblastic leukemia (CCRF-CEM), human splenic B-lymphoblastoid cells (WIL-2NS), human acute B-lymphoblastic leukemia (CCRF-SB), skin melanoma (SK-MEL-28), and prostate carcinoma (DU145) cell lines (CC50 = 0.5 ,M, 0.4 ± 0.05 ,M, 0.6 ± 0.05 ,M, 0.4 ± 0.1 ,M, and 0.8 ± 0.2 ,M, respectively), meanwhile, 9a, b, 14a, b, and 23 showed significant activity against the CCRF-SB cell lines (CC50 = 0.6 ± 0.06 ,M, 0.7 ± 0.05 ,M, 0.6 ± 0.05 ,M, and 0.8 ± 0.15 ,M, respectively). Further, 19 exhibited activity against the CCRF-CEM cell line (CC50 = 0.4 ± 0.05 ,M). [source]


    Synthesis and Biological Evaluation of Some Polymethoxylated Fused Pyridine Ring Systems as Antitumor Agents

    ARCHIV DER PHARMAZIE, Issue 10 2009
    Sherif A. F. Rostom
    Abstract A series of 3,5- bis(arylidene)-4-piperidones like chalcone analogues carrying variety of methoxylated aryl groups, pyrazolo[4,3- c]pyridines, pyrido[4,3- d]pyrimidines, and pyrido[3,2- c]pyridines, carrying an arylidene moiety, and some pyrano[3,2- c]pyridines, like flavone and coumarin isosteres, were synthesized and screened for their in-vitro antitumor activity at the National Cancer Institute (NCI, USA). The tested compounds 7, 9, 10, 12, 13, 15, 17, and 19 exhibited a broad spectrum of antitumor activity. Compounds belonging to the pyrazolo[4,3- c]pyridine series proved to be more active than those of the pyrido[3,2- c]pyridine and pyrano[3,2- c]pyridine analogues, in which the monomethoxylated derivatives showed better antitumor activity when compared with their corresponding dimethoxylated congeners. Compound 7 is considered to be the most active member identified in this study with a broad spectrum of activity against 22 different tumor cell lines belonging to the nine subpanels employed, and a particular effectiveness against the breast cancer T-47D cell line (GI 54.7%). The pyrano[3,2- c]pyridine heterocyclic system 19 proved to be the most active antitumor agent among the six-membered fused pyridines, with variable activity against 18 different tumor cell lines, and special activity against the non-small cell lung cancer Hop-92 and ovarian cancer OVCAR-4 cell lines (GI values 63.9 and 48.5%, respectively). [source]


    Disubstituted 4(3H) Quinazolones: A Novel Class of Antitumor Agents

    CHEMICAL BIOLOGY & DRUG DESIGN, Issue 3 2009
    Vikas Srivastava
    A series of disubstituted 4(3H) quinazolines were designed for potential application in tumors. Firstly, N -benzoyl anthranilic acid is formed, which undergoes cyclization in the presence of pyridine. Subsequently, nucleophilic attack by semicarbazide on the carbonyl carbon gives 2-substituted 3-carbamido 4(3H) quinazolones, which gives final compound with appropriate substitution. The final as well as intermediate products were confirmed by NMR, FT-IR, and mass spectrometry. In vitro toxicity was performed with different cell lines and showed that the connection of hydrophilic styryl to quinazoline moiety increases its efficacy. [source]


    ChemInform Abstract: Polar 3-Alkylidene-5-pivaloyloxymethyl-5,-hydroxymethyl-,-lactones as Protein Kinase C Ligands and Antitumor Agents.

    CHEMINFORM, Issue 37 2010
    Jeewoo Lee
    Abstract The synthesis and activity of 31 members of the title series are presented. [source]


    ChemInform Abstract: Synthesis of (3-Amino-7-chloro-8-methyl-1,1-dioxo-4H-1,5,2-benzo [f]dithiazepin-4-ylidene)acetic Acid Derivatives as Potential Antitumor Agents.

    CHEMINFORM, Issue 21 2008
    Z. Brzozowski
    Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source]


    Synthesis and Evaluation of 3-Methyl-4-oxo-6-phenyl-4,5,6,7-tetrahydrobenzofuran-2-carboxylic Acid Ethyl Ester Derivatives as Potent Antitumor Agents.

    CHEMINFORM, Issue 48 2005
    Ichiro Hayakawa
    Abstract For Abstract see ChemInform Abstract in Full Text. [source]


    Synthesis and Biological Evaluation of a Novel Phenyl Substituted Sydnone Series (VII) as Potential Antitumor Agents.

    CHEMINFORM, Issue 47 2003
    Christopher S. Dunkley
    No abstract is available for this article. [source]


    ChemInform Abstract: Aziridinyl Quinone Antitumor Agents Based on Indoles and Cyclopent[b]indoles: Structure,Activity Relationships for Cytotoxicity and Antitumor Activity.

    CHEMINFORM, Issue 8 2002
    Edward B. Skibo
    Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source]


    Increased hepatotoxicity of tumor necrosis factor,related apoptosis-inducing ligand in diseased human liver,

    HEPATOLOGY, Issue 5 2007
    Xandra Volkmann
    Tumor necrosis factor,related apoptosis-inducing ligand (TRAIL) induces apoptosis in tumor cells but not in most normal cells and has therefore been proposed as a promising antitumor agent. Recent experiments suggested that isolated primary human hepatocytes but not monkey liver cells are susceptible to certain TRAIL agonists, raising concerns about the use of TRAIL in cancer treatment. Whether TRAIL indeed exerts hepatotoxicity in vivo and how this is influenced by chemotherapeutic drugs or liver disease are completely unknown. Employing different forms of recombinant TRAIL, we found that the cytokine can induce proapoptotic caspase activity in isolated human hepatocytes. However in marked contrast, these different TRAIL preparations induced little or no cytotoxicity when incubated with tissue explants of fresh healthy liver, an experimental model that may more faithfully mimic the in vivo situation. In healthy liver, TRAIL induced apoptosis only when combined with histone deacetylase inhibitors. Strikingly, however, TRAIL alone triggered massive apoptosis accompanied by caspase activation in tissue explants from patients with liver steatosis or hepatitis C viral infection. This enhanced sensitivity of diseased liver was associated with an increased expression of TRAIL receptors and up-regulation of proapoptotic Bcl-2 proteins. Conclusion: These results suggest that clinical trials should be performed with great caution when TRAIL is combined with chemotherapy or administered to patients with inflammatory liver diseases. (HEPATOLOGY 2007.) [source]


    Novel indoloquinoline derivative, IQDMA, inhibits STAT5 signaling associated with apoptosis in K562 cells

    JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 6 2008
    Sheng-Huei Yang
    Abstract N,-(11H-indolo[3,2-c]quinolin-6-yl)- N,N -dimethylethane-1,2-diamine (IQDMA), an indoloquinoline derivative, synthesized in our laboratory, has been demonstrated to be an effective antitumor agent in human leukemia cells. In the present study, treatment with IQDMA inhibited phosphorylation of epidermal growth factor receptor (EGFR), Src, Bcr-Abl, and Janus-activated kinase (JAK2) in a time-dependent manner. IQDMA also degraded JAK2 protein. Moreover, signal transducer and activator of transcription 5 (STAT5) signaling were also blocked by IQDMA. However, IQDMA did not inhibit other oncogenic and tumor survival pathways such as those mediated by Akt and extracellular signal-regulated kinase 1/2. Furthermore, IQDMA upregulated the expression of p21 and p27 and downregulated the expression of cyclin D1, myeloid cell leukemia-1(Mcl-1), Bcl-XL, and vascular endothelial growth factor (VEGF). Taken together, these results indicate that IQDMA causes significant induction of apoptosis in K562 cells via downregulation of EGFR, Src, Bcr-Abl, JAK2, and STAT5 signaling and modulation of p21, p27, cyclin D1, Mcl-1, Bcl-XL, and VEGF proteins. Thus, IQDMA appears to be a potential therapeutic agent for treating leukemia K562 cells. © 2008 Wiley Periodicals, Inc. J Biochem Mol Toxicol 22:396,404, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20254 [source]


    Antitumor activity of chloroform fraction of Scutellaria barbata and its active constituents

    PHYTOTHERAPY RESEARCH, Issue 9 2007
    Jianqing Yu
    Abstract Scutellaria barbata (SB) is widely used as an antitumor agent in China, but the antitumor components of SB are still unclear. The antitumor activity of various fractions of an ethanol extract of SB was studied in six human malignant cell lines. Bio-based assays showed that non-polar and low-polar solvent fractions of SB had dose-dependent cytotoxicities on six cancer cell lines. The IC50 values of these fractions on the cancer cell lines tested ranged from 16 to 70 µg/mL after 48 h of treatment. Among them, the chloroform fraction (CE-SB) had the strongest cytotoxicity on cancer cell lines with a lower cytotoxic effect on a normal liver cell line. Bel-7402 cell apoptosis induced by CE-SB was examined using Hoechst 33258 staining, agarose gel electrophoresis and flow cytometry. CE-SB dose-dependently decreased the S phase content. Treatment with CE-SB caused cytochrome c release and activation of caspase-9. The antitumor activity of CE-SB in vivo was also evaluated. At 60 mg/kg/day, CE-SB significantly inhibited the solid tumor proliferation and increased the life span of ascites tumor bearing mice (p < 0.01). CE-SB was subjected to bioassay-guided isolation of the active compounds by chromatography on silica gel and Sephadex LH-20. Phytol, wogonin, luteolin and hispidulin were obtained as cytotoxic constituents. Copyright © 2007 John Wiley & Sons, Ltd. [source]


    Metabolism of a sulfur-containing heteroarotionoid antitumor agent, SHetA2, using liquid chromatography/tandem mass spectrometry

    RAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 21 2008
    Zhongfa Liu
    SHetA2 {[(4-nitrophenyl)amino][2,2,4,4-tetramethylthiochroman-6-yl)amino]methanethione], NSC 726189}, a sulfur-containing heteroarotinoid, selectively inhibits cancer cell growth and induces apoptosis without activation of nuclear retinoic acid receptors (RARs). The objective of this study was to investigate its in vitro metabolism in rat and human liver microsomes and in vivo metabolism in the mouse and rat using liquid chromatography-ultraviolet/multi-stage mass spectrometry (LC-UV/MSn) on an ion-trap mass spectrometer coupled with a photo-diode array (PDA) detector. In vitro, in the absence of glutathione (GSH), oxidation of the four aliphatic methyl groups of SHetA2 yielded one mono-, two di-, and one tri-hydroxylated SHetA2 metabolites, which were identified based on their UV and multi-stage mass spectra. In the presence of GSH, in addition to these primary oxidative metabolites, four GSH adducts of SHetA2 and a novel rare form thioether GSH adduct was detected and characterized. In vivo, the monohydroxylated SHetA2 metabolites were also detected in mouse and rat plasma and two GSH adducts were detected in rat liver following intravenous (i.v.) bolus administration of SHetA2 at 40,mg/kg. Copyright © 2008 John Wiley & Sons, Ltd. [source]


    Metabolite identification of a new antitumor agent icotinib in rats using liquid chromatography/tandem mass spectrometry

    RAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 14 2008
    Zhongmin Guan
    Icotinib, 4-[(3-ethynylphenyl)amino]-6,7-benzo-12-crown-4-quinazoline, is a new antitumor agent. The metabolic pathway of icotinib in rats was studied using liquid chromatography/tandem mass spectrometry (LC/MSn) analysis. Full scan and selected ion monitoring modes were used to profile the possible metabolites of icotinib in rat urine, feces and bile samples. Four phase I metabolites (M1,M4) and two phase II metabolites (M5, M6) were detected and characterized. Multiple-stage mass spectrometry and nuclear magnetic resonance (NMR) spectrometry were employed to elucidate structures of metabolites. Icotinib was metabolized to open the crown ether ring to form the main phase I metabolites. During metabolism, a reactive metabolite was formed. Using semicarbazide as a trapping agent, an intermediate arising from opening of the crown ether ring was detected as an aldehyde product by LC/MS/MS. These data indicated that ring opening of the crown ether was triggered by hydroxylation at the 8,-position of the ring to form a hemiacetal intermediate, which was further oxidized or reduced. Finally, the metabolic pathway of icotinib in rats was proposed. Copyright © 2008 John Wiley & Sons, Ltd. [source]


    Thieno[2,3- d]pyrimidines in the Synthesis of Antitumor and Antioxidant Agents

    ARCHIV DER PHARMAZIE, Issue 5 2010
    Ashraf A. Aly
    Abstract Dimethyl acetylenedicarboxylate, ethyl propiolate, and E -dibenzoylethylene react with thienopyrimidines (cyclo-pentyl, -hexyl, and -heptyl) derivatives to form thiazolo[3,2- a]thieno-[2,3- d]pyrimidin-2-ylidene) acetates, thieno[2,3- d]pyrimidin-2-ylthioacrylates, and thieno[2,,3,:4,5]pyrimido[2,1- b][1,3]thiazin-6-ones, respectively. Reactions proceed via cyclization and thio-addition processes. Some derivatives of thienopyrimidines showed high inhibition of Hep-G2 cell growth compared with the growth of untreated control cells. However, the fused heptyl of thienopyrimidothiazines indicates a promising specific antitumor agent against Hep-G2 cells with IC50 < 20 ,M. [source]


    Synthesis and Biological Evaluation of Some Polymethoxylated Fused Pyridine Ring Systems as Antitumor Agents

    ARCHIV DER PHARMAZIE, Issue 10 2009
    Sherif A. F. Rostom
    Abstract A series of 3,5- bis(arylidene)-4-piperidones like chalcone analogues carrying variety of methoxylated aryl groups, pyrazolo[4,3- c]pyridines, pyrido[4,3- d]pyrimidines, and pyrido[3,2- c]pyridines, carrying an arylidene moiety, and some pyrano[3,2- c]pyridines, like flavone and coumarin isosteres, were synthesized and screened for their in-vitro antitumor activity at the National Cancer Institute (NCI, USA). The tested compounds 7, 9, 10, 12, 13, 15, 17, and 19 exhibited a broad spectrum of antitumor activity. Compounds belonging to the pyrazolo[4,3- c]pyridine series proved to be more active than those of the pyrido[3,2- c]pyridine and pyrano[3,2- c]pyridine analogues, in which the monomethoxylated derivatives showed better antitumor activity when compared with their corresponding dimethoxylated congeners. Compound 7 is considered to be the most active member identified in this study with a broad spectrum of activity against 22 different tumor cell lines belonging to the nine subpanels employed, and a particular effectiveness against the breast cancer T-47D cell line (GI 54.7%). The pyrano[3,2- c]pyridine heterocyclic system 19 proved to be the most active antitumor agent among the six-membered fused pyridines, with variable activity against 18 different tumor cell lines, and special activity against the non-small cell lung cancer Hop-92 and ovarian cancer OVCAR-4 cell lines (GI values 63.9 and 48.5%, respectively). [source]


    Small-Sample Inference for Incomplete Longitudinal Data with Truncation and Censoring in Tumor Xenograft Models

    BIOMETRICS, Issue 3 2002
    Ming Tan
    Summary. In cancer drug development, demonstrating activity in xenograft models, where mice are grafted with human cancer cells, is an important step in bringing a promising compound to humans. A key outcome variable is the tumor volume measured in a given period of time for groups of mice given different doses of a single or combination anticancer regimen. However, a mouse may die before the end of a study or may be sacrificed when its tumor volume quadruples, and its tumor may be suppressed for some time and then grow back. Thus, incomplete repeated measurements arise. The incompleteness or missingness is also caused by drastic tumor shrinkage (<0.01 cm3) or random truncation. Because of the small sample sizes in these models, asymptotic inferences are usually not appropriate. We propose two parametric test procedures based on the EM algorithm and the Bayesian method to compare treatment effects among different groups while accounting for informative censoring. A real xenograft study on a new antitumor agent, temozolomide, combined with irinotecan is analyzed using the proposed methods. [source]


    Electrochemical study on interaction of vincristine with tubulin

    CHINESE JOURNAL OF CHEMISTRY, Issue 11 2001
    Yong Yu
    Abstract In Tris (0.005 mol/L)-NaCl (0.05 mol/L) buffer solution (pH = 7.10), keeping temperature at 37°C, a highly sensitive reduction peak of the antitumor agent was obtained by linear sweep voltammetry. The peak potential is-1.56 V (vs. SCE). The peak current is proportional to the concentration of vincristine over the range of 2.1 ± 10,7 -4.2 ± 10,6 mol/L with the detection limit of 1.0 ± 10,7 mol/L. The behavior of the binding of vincristine to tubulin was studied. The results showed that the reaction of tubulin dimer with vincristine formed an electrochemically active complex to be 1:2. Its stability constant is 2.5 ± 1014. The reduction process of the complex is irreversible with adsorptive characteristics. [source]


    Amphiphilic block copolymer micelles for nanoscale drug delivery

    DRUG DEVELOPMENT RESEARCH, Issue 1 2006
    Glen S. Kwon
    Abstract Amphiphilic block copolymers can assemble into supramolecular core-shell structures, termed ABC micelles, that have proven utility in drug delivery, particularly for drug solubilization. Several examples have entered clinical trials, attesting to the biocompatibility of ABCs and the potential advantages for drug delivery, e.g., low toxicity relative to Cremophor® EL, a surfactant commonly used for drug solubilization. Several examples of ABC micelles demonstrate potential for prolonged circulation in blood. Coupled with novel strategies toward controlled release of drug, nanoscale ABC micelles have tremendous potential for the targeting of antitumor agents, many of which are poorly water soluble and possess dose-limiting toxicity. Drug Dev. Res. 67:15,22, 2006. © 2006 Wiley-Liss, Inc. [source]


    The Development of a Convergent and Efficient Enantioselective Synthesis of the Bengamides via a Common Polyol Intermediate

    HELVETICA CHIMICA ACTA, Issue 12 2002
    Robert
    An efficient, general synthetic route to the bengamide family of antitumor agents from a common polyol thioester is described. Consecutive aldol condensations afford the protected polyol thioester side chain suitable for coupling to the bengamides. A novel chiral-phase-transfer-catalyzed enantioselective alkylation affords the properly functionalized caprolactams required for the synthesis of more-complex members of the bengamide family. Use of the methyl 2-naphthyl ether protecting group, compatible with the boron Lewis acids required for enantioselective aldol condensation, allows direct access to all the bengamides. [source]


    99mTc-MIBI imaging for prediction of therapeutic effects of second-generation MDR1 inhibitors in malignant brain tumors

    INTERNATIONAL JOURNAL OF CANCER, Issue 12 2007
    Toshio Sasajima
    Abstract The aim of this study was to explore whether 99mTc-methoxyisobutylisonitrile (99mTc-MIBI) is suitable to elucidate multidrug resistance and prediction of potentiation of antitumor agents by second-generation MDR1 inhibitors (PSC833, MS-209) in malignant brain tumors in rat. Malignant tumor cells (RG2 and C6 gliomas, Walker 256 carcinoma) were incubated with low dose vincristine (VCR) to induce multidrug resistance. MTT assay demonstrated a significant increase of surviving fractions in VCR-resistant sublines compared to those of drug-naive cells. Reverse transcriptase polymerase chain reaction revealed higher expression of MDR1 mRNA in VCR-resistant cells than drug-naive cells in each line. Volume distribution (Vd) of 99mTc-MIBI was negatively correlated with MDR1 mRNA expression among drug-naive and VCR-resistant cells. MDR1 inhibitors decreased surviving fractions and increased Vd of 99mTc-MIBI significantly in VCR-resistant sublines, whereas MDR1 mRNA expression was unchanged. These findings indicate that 99mTc-MIBI efflux was functionally suppressed by MDR1 inhibitors. Autoradiographic images of 99mTc-MIBI revealed higher uptake in drug-naive cells at basal ganglia compared with VCR-resistant cells at the opposite basal ganglia of rats. Oral administration of the second-generation MDR1 inhibitors significantly increased 99mTc-MIBI accumulation of both tumors. Therapeutic effects of VCR with or without the MDR1 inhibitors were also evaluated autoradiographically using 14C-methyl- L -methionine (14C-Met) and MIB-5 index. 14C-Met uptake and MIB-5 index of both tumors treated with VCR following the MDR1 inhibitor treatment significantly decreased compared with tumors treated with VCR alone. Analysis of 99mTc-MIBI accumulation is considered informative for detecting MDR1-mediated drug resistance and for monitoring the therapeutic effects of MDR1 inhibitors in malignant brain tumors. © 2007 Wiley-Liss, Inc. [source]


    Novel 3-benzoyl-2-piperazinylquinoxaline derivatives as potential antitumor agents

    JOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 3 2006
    Sandra Piras
    A series of new benzoylquinoxaline derivatives (7-26) was synthesized and evaluated for antitumor activity against a panel of 60 human cell lines at the NCI of Bethesda. Among the compounds which have passed the preliminary screening, compound 23 exhibited the best profile and growth inhibition activity at 100 - 10 ,M. The compounds were then tested towards a folate-dependent enzymes bio-library including Thymidylate synthases enzymes and human Dihydrofolate reductase at 10 ,M. The most of compounds exhibited a moderate inhibitory activity towards all or some of the enzymes tested with detectable inhibition constants (Ki) values in the range of 0.6-70 ,M. Compounds 21, 23, 24 showed Ki in the range of 10-38 ,M against both hDHFR and hTS. [source]


    Statins can modulate effectiveness of antitumor therapeutic modalities

    MEDICINAL RESEARCH REVIEWS, Issue 1 2010
    Marek Jakobisiak
    Abstract Despite significant, frequently very strong, antiproliferative and tumoricidal effects of statins demonstrated in vitro, their antitumor effects in animal models are modest, and their efficacy in clinical trials has not been proven. As such, statins seem unlikely to be ever regarded as antitumor agents. However, statins are regularly taken by many elderly cancer patients for the prevention of cardiovascular events. Owing to their pleiotropic effects in normal and tumor cells, statins interact in various ways with many antitumor treatment modalities, either potentiating or diminishing their effectiveness. Elucidation of these interactions might affect the choice of treatment to be planned in cancer patients as some combinations might be contraindicated, whereas others might elicit potentiated antitumor effects but at a cost of increased general toxicity. Some other combinations might induce either comparable or even stronger antitumor effects, but with a beneficial concomitant reduction of specific side effects. Most of the studies reviewed in this article have been carried in vitro or in experimental tumor models, but clinical relevance of the findings is also discussed. © 2009 Wiley Periodicals, Inc. Med Res Rev, 30, No. 1, 102,135, 2010 [source]


    Carbonic anhydrase IX: A new druggable target for the design of antitumor agents

    MEDICINAL RESEARCH REVIEWS, Issue 3 2008
    Jean-Yves Winum
    Abstract Carbonic anhydrases (CAs, EC 4.2.1.1) are a family of enzymes widespread in all life kingdoms. In mammals, isozyme CA IX is highly overexpressed in many cancer types being present in few normal tissues. Its expression is strongly induced by hypoxia present in many tumors, being regulated by the HIF transcription factor and correlated with a poor response to classical chemo- and radiotherapies. CA IX was recently shown to contribute to acidification of the tumor environment, by efficiently catalyzing the hydration of carbon dioxide to bicarbonate and protons with its extracellularly situated active site, leading both to the acquisition of metastasic phenotypes and to chemoresistance with weakly basic anticancer drugs. Inhibition of this enzymatic activity by specific and potent inhibitors was shown to revert these acidification processes, establishing a clear-cut role of CA IX in tumorigenesis. The development of a wide range of potent and selective CA IX inhibitors belonging to diverse chemical classes, such as membrane-impermeant, fluorescent or metal-containing such agents, could thus provide useful tools for highlighting the exact role of CA IX in hypoxic cancers, to control the pH (im)balance of tumor cells, and to develop novel diagnostic or therapeutic applications for the management of tumors. Indeed, both fluorescent inhibitors or positively charged, membrane impermeant sulfonamides have been recently developed as potent CA IX inhibitors and used as proof-of-concept tools for demonstrating that CA IX constitutes a novel and interesting target for the anticancer drug development. © 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 3, 445,463, 2008 [source]


    DNA minor groove binders as potential antitumor and antimicrobial agents

    MEDICINAL RESEARCH REVIEWS, Issue 4 2004
    Pier Giovanni Baraldi
    Abstract DNA minor groove binders constitute an important class of derivatives in anticancer therapy. Some of these compounds form noncovalent complexes with DNA (e.g., distamycin A, Hoechst 33258, and pentamidine) while others DNA-binding compounds (such as CC-1065) cause cleavages in the DNA backbone. In this article, we have reviewed the minor groove binders currently in preclinical evaluation in the last years. Diarylamidines such as DAPI, berenil, and pentamidine; bis-benzimidazoles such as Hoechst 33258; ecteinascidins, pyrrololo [2,1- c]-[1,4]-benzodiazepines (PBDs), CC-1065, and distamycins are the classes discussed in this review article. A special section has been dedicated to hybrid molecules resulted by the combination of two minor groove binders, especially for derivatives of naturally occurring antitumor agents, such as anthramycin or the alkylating unit of the antibiotic CC-1065, and distamycin frames. © 2004 Wiley Periodicals, Inc. Med Res Rev, 24, No. 4, 475,528, 2004 [source]