Abstract:
:Ergot alkaloids are psychoactive and vasoconstricting agents of the fungus Claviceps purpurea causing poisoning such as ergotism in medieval times (St. Anthony's Fire). This class of substances also inhibits tumor growth in vitro and in vivo, though the underlying mechanisms are unclear as yet. We investigated six ergot alkaloids (agroclavine, ergosterol, ergocornin E, ergotamine, dihydroergocristine, and 1-propylagroclavine tartrate) for their cytotoxicity towards tumor cell lines of the National Cancer Institute, USA. 1-Propylagroclavine tartrate (1-PAT) revealed the strongest cytotoxicity. Out of 76 clinically established anticancer drugs, cross-resistance was found between the ergot alkaloids and 6/7 anti-hormonal drugs (=85.7 %) and 5/15 DNA-alkylating drugs (=33.3 %). The IC50 values for the six alkaloids were not correlated to well-known determinants of drug resistance, such as proliferative activity (as measured by cell doubling times, PCNA expression, and cell cycle distribution), the multidrug resistance-mediating P-glycoprotein/MDR1 and expression or mutations of oncogenes and tumor suppressor genes (EGFR, RAS, TP53). While resistance of control drugs (daunorubicin, cisplatin, erlotinib) correlated with these classical resistance mechanisms, ergot alkaloids did not. Furthermore, COMPARE and hierarchical cluster analyses were performed of mRNA microarray data to identify genes correlating with sensitivity or resistance to 1-PAT. Twenty-three genes were found with different biological functions (signal transducers, RNA metabolism, ribosome constituents, cell cycle and apoptosis regulators etc.). The expression of only 3/66 neuroreceptor genes correlated with the IC50 values for 1-PAT, suggesting that the psychoactive effects of ergot alkaloids may not play a major role for the cytotoxic activity against cancer cells. In conclusion, the cytotoxicity of ergot alkaloids is not involved in classical mechanisms of drug resistance opening the possibility to bypass resistance and to treat otherwise drug-resistant and refractory tumors. The modes of action are multifactorial, which is a typical feature of many natural compounds.
journal_name
Invest New Drugsjournal_title
Investigational new drugsauthors
Mrusek M,Seo EJ,Greten HJ,Simon M,Efferth Tdoi
10.1007/s10637-014-0168-4subject
Has Abstractpub_date
2015-02-01 00:00:00pages
32-44issue
1eissn
0167-6997issn
1573-0646journal_volume
33pub_type
杂志文章abstract::Bryostatin 1 (Bryo) is a naturally occurring macrocyclic lactone with antineoplastic activity. Like the phorbol ester 12-O-tetradecanoyl-phorbol 13-acetate (TPA) it directly activates the calcium- and phospholipid-dependent protein kinase C (PKC), thus generating a number of different cellular responses. We investigat...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00873230
更新日期:1994-01-01 00:00:00
abstract::Background DR5 is a transmembrane receptor that transduces extracellular ligand-binding to activate apoptosis signaling cascades. This phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of a new monoclonal antibody potent DR5 agonist, DS-8273a, in subjects with advanced solid...
journal_title:Investigational new drugs
pub_type: 杂志文章,多中心研究
doi:10.1007/s10637-016-0420-1
更新日期:2017-06-01 00:00:00
abstract:PURPOSE:To compare two different infusion schedules of phenylacetate (PA) in patients with primary brain tumors and to assess the feasibility of the administration in a multi-institutional setting. PATIENTS AND METHODS:Adult patients with recurrent primary brain tumors were treated with PA on two different schedules. ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1023/a:1026299118067
更新日期:2003-11-01 00:00:00
abstract:BACKGROUND:This Phase-I-study aimed to determine the recommended Phase-II-dosing-schedule of LY2334737, an oral gemcitabine prodrug, in patients with advanced/metastatic solid tumors. Pharmacokinetics, cytokeratin-18 (CK18) levels, genetic polymorphisms, and antitumor activity were additionally evaluated. METHODS:Pati...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-015-0286-7
更新日期:2015-12-01 00:00:00
abstract::The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (INNO-206) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that is being assessed clinically. The prodrug binds rapidly to circulating serum albumin and releases doxorubicin selectively at the tumor site. This novel mechanism may p...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-008-9208-2
更新日期:2010-02-01 00:00:00
abstract::Thirty-two patients with advanced epidermoid carcinoma of the esophagus were treated with ifosfamide (1.50 gm/m2 daily x 5 days) with uroprotective mesna in a phase II study. Eighteen patients were previously untreated. Of 28 evaluable patients, two (7%) had partial remissions lasting 2+ and 6+ months. Toxicity was pr...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00175406
更新日期:1988-09-01 00:00:00
abstract::A short-term antimetabolic assay based upon the inhibition of incorporation of nucleic acid precursors was used to compare the cytotoxicity of a new halogenated anthracycline, 4'-iodo-4'-deoxydoxorubicin (IDX), with that of its parent compound doxorubicin (DX) on human colo-rectal carcinoma specimens. IDX showed a mar...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00177248
更新日期:1990-05-01 00:00:00
abstract::Apoptin is a nonstructural protein encoded by one of the three open reading frames of the chicken anemia virus genome. It has attracted a great deal of interest due to its ability to induce apoptosis in multiple transformed and malignant mammalian cell lines without affecting primary and non-transformed cells. However...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-017-0431-6
更新日期:2017-06-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-009-9357-y
更新日期:2011-04-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00175387
更新日期:1984-01-01 00:00:00
abstract::Spirogermanium (NSC 192965) is a new metallic investigational anticancer drug of novel heterocyclic structure. Although its mode of action has not been fully elucidated, it appears that spirogermanium is not a phase or cell cycle specific drug and inhibits DNA, RNA and protein synthesis, the protein synthesis being th...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00208894
更新日期:1983-01-01 00:00:00
abstract::Aims A primary objective of this study was to investigate the effect of single and multiple doses of alisertib, an investigational Aurora A kinase inhibitor, on the QTc interval in patients with advanced malignancies. The dose regimen used was the maximum tolerated dose which was also the recommended phase 3 dose (50 ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-017-0498-0
更新日期:2018-04-01 00:00:00
abstract::ALK-positive anaplastic large cell lymphoma (ALCL) represents a subset of non-Hodgkin's lymphoma that is treated with crizotinib, a dual ALK/MET inhibitor. Despite the remarkable initial response, ALCLs eventually develop resistance to crizotinib. ALK inhibitor resistance in tumors is a complex and heterogeneous proce...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-019-00802-7
更新日期:2020-06-01 00:00:00
abstract::This study was designed to test the hypothesis that specific inhibition of cathepsins B and L will cause death of neuroblastoma cells. Five compounds that differ in mode and rate of inhibition of these two enzymes were all shown to cause neuroblastoma cell death. Efficacy of the different compounds was related to thei...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-012-9826-6
更新日期:2013-02-01 00:00:00
abstract::Purpose The aim of this study is to detect apoptotic and cytotoxic/antiproliferative effects of a ligand substance and its metal derivatives. The substances were investigated by using an h-ras oncogene transformed rat embryo fibroblast cell line (5RP7). Methods The cytotoxic influences of dipyrido[3,2-a:2',3'c]phenazi...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-017-0559-4
更新日期:2018-10-01 00:00:00
abstract::Toxicity in the form of marrow suppression has hampered the investigation of intensive chemotherapy as it applies to the treatment of solid tumors. The use of autologous marrow rescue to ameliorate protracted aplasia permits the application of high dose chemotherapy to the treatment of solid tumors. We review the theo...
journal_title:Investigational new drugs
pub_type: 杂志文章,评审
doi:10.1007/BF00177416
更新日期:1983-01-01 00:00:00
abstract::We have recently developed a liposomal nanoparticle (LNP) formulation of irinotecan based on loading method that involves formation of a complex between copper and the water soluble camptothecin. The loading methodology developed for irinotecan was evaluated to develop a LNP topotecan formulation (referred to herein a...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-012-9832-8
更新日期:2013-02-01 00:00:00
abstract::Fifteen patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck received a 5 day continuous I.V. infusion of 6-thioguanine repeated every five weeks. Dose limiting toxicity was primarily hematological with grade III/IV leucopenia and thrombocytopenia seen in seven patients. Nausea and vo...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1007/BF00873122
更新日期:1992-07-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-010-9569-1
更新日期:2012-04-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-015-0240-8
更新日期:2015-06-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1023/a:1006128024879
更新日期:1998-01-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1023/a:1020662113061
更新日期:2002-11-01 00:00:00
abstract::Infantile hemangioma is the most common vascular tumor of childhood. It is characterized by clinical expansion of endothelial cells and promoted by angiogenic factors. Luteolin is a flavonoid compound that carries anti-cancer and anti-angiogenesis properties. The study aimed to investigate the effect of luteolin in tr...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-020-01052-8
更新日期:2021-01-07 00:00:00
abstract::Monoclonal antibodies directed against the immune checkpoint protein cytotoxic T-lymphocyte antigen-4 (CTLA-4; CD152) have been investigated in metastatic melanoma and other cancers and have shown promising results. Inhibition of CTLA-4 characteristically induces well-known side effects called "immune-related adverse ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-014-0092-7
更新日期:2014-08-01 00:00:00
abstract::Background AR-67 is a novel camptothecin analogue at early stages of drug development. The phase 1 clinical trial in cancer patients with solid tumors was completed and a population pharmacokinetic model (POP PK) was developed to facilitate further development of this investigational agent. Methods Pharmacokinetic dat...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-019-00744-0
更新日期:2019-12-01 00:00:00
abstract::Diflubenzuron (DFB) and Clanfenur (CFN) belong to a group of compounds called Benzoylphenyl Ureas (BPUs). Several BPUs regulate cell growth in insects and/or inhibit growth of B-16 murine melanomas. In view of potential clinical use for these compounds, DFB and CFN were selected as examples of BPUs and tested for effe...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00874426
更新日期:1993-11-01 00:00:00
abstract::Background PF-06840003 is a highly selective indoleamine 2, 3-dioxygenase (IDO1) inhibitor with antitumor effects in preclinical models. This first-in-human phase 1 study evaluated safety, pharmacokinetics/pharmacodynamics, and preliminary efficacy in recurrent malignant glioma to determine the maximum tolerated dose ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-020-00950-1
更新日期:2020-12-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1007/s10637-005-1439-x
更新日期:2005-08-01 00:00:00
abstract::UCN-01 is undergoing Phase I evaluation and is a candidate for combination strategies in the clinic. UCN-01 has been shown to have a variety of effects on cellular targets and the cell cycle. It has also been reported to sensitize cells to several clinical drugs in vitro, possibly in a manner related to p53 status. Th...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1023/a:1006313611677
更新日期:2000-05-01 00:00:00
abstract::VEGF signaling through VEGFR-2 is the major factor in glioblastoma angiogenesis. CT-322, a pegylated protein engineered from the 10th type III human fibronectin domain, binds the VEGFR-2 extracellular domain with high specificity and affinity to block VEGF-induced VEGFR-2 signaling. This study evaluated CT-322 in an o...
journal_title:Investigational new drugs
pub_type: 杂志文章,随机对照试验
doi:10.1007/s10637-014-0186-2
更新日期:2015-02-01 00:00:00