Abstract：
:We have previously described a human pancreatic-ribonuclease variant, named PE5, which carries a non-contiguous extended bipartite nuclear localization signal. This signal comprises residues from at least three regions of the protein. We postulated that the introduction of this signal in the ribonuclease provides it with cytotoxic activity because although the variant poorly evades the ribonuclease inhibitor in vitro, it is routed to the nucleus, which is devoid of the inhibitor. In this work, we have investigated the relationship between the cytotoxicity produced by PE5 and its ability to reach the nucleus. First, we show that this enzyme, when incubated with HeLa cells, specifically cleaves nuclear RNA while it leaves cytoplasmic RNA unaffected. On the other hand, we have created new variants in which the residues of the nuclear localization signal that are important for the nuclear transport have been replaced. As expected, the individual changes produce a significant decrease in the cytotoxicity of the resulting variants. We conclude that the nuclear transport of PE5 is critical for its cytotoxicity. Therefore, routing a ribonuclease to the nucleus is an alternative strategy to endow it with cytotoxic activity.
journal_name
Invest New Drugsjournal_title
Investigational new drugsauthors
Tubert P,Rodríguez M,Ribó M,Benito A,Vilanova Mdoi
10.1007/s10637-010-9426-2subject
Has Abstractpub_date
2011-10-01 00:00:00pages
811-7issue
5eissn
0167-6997issn
1573-0646journal_volume
29pub_type
杂志文章abstract：BACKGROUND:Gemcitabine is a pro-drug that has to be phosphorylated to gemcitabine-triphosphate in order to exhibit its antineoplastic activity. This reaction involves the enzyme deoxycytidine kinase which is saturated at plasma concentrations following standard 30-min infusions. Pharmacological studies indicate that pr...
journal_title：Investigational new drugs
pub_type： 临床试验,杂志文章
doi：10.1007/s10637-005-5859-4
更新日期：2005-03-01 00:00:00
abstract：:To explore the clinical significance of the level of HER2/neu gene amplification in a homogenous cohort of 33 patients with HER2-positive metastatic breast cancer (MBC) and available tumor samples treated with a trastuzumab-based regimen, we retrospectively performed dual-color fluorescence in-situ hybridization test ...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-008-9155-y
更新日期：2009-04-01 00:00:00
abstract：:Artemisinin and its derivatives are well known antimalarial drugs, particularly useful after resistance to traditional antimalarial pharmaceuticals has started to occur in Plasmodium falciparum. In recent years, anticancer activity of artemisinin has been reported both in vitro and in vivo. Artemisinin has inhibitory ...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-008-9188-2
更新日期：2009-10-01 00:00:00
abstract：:Myricetin is a naturally omnipresent benzo-α-pyrone flavonoids derivative; has potent anticancer activity. Receptor tyrosine kinases family provides the decisive role in cancer initiation and progression. These receptors have recently caught the attention of the researchers as an attractive target to combat cancer, ow...
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
abstract：:Tea (Camellia sinensis) is one of the most widely used beverages worldwide and tea consumption has been shown to have an inverse correlation to the incidence of human cancers in epidemiological and experimental studies. In the present study, the protective effects of green tea polyphenols (GTP) and black tea polypheno...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-008-9204-6
更新日期：2009-12-01 00:00:00
abstract：:Menogarol is a new anthracycline undergoing phase I clinical trial. We report here the lethality after 2 hr exposure to 2 drug combinations of menogarol and several antitumor agents. A new statistical procedure was used to identify synergistic combinations. Most of these combinations were additive, except for menogaro...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/BF00179427
更新日期：1985-01-01 00:00:00
abstract：:Posterior reversible encephalopathy syndrome (PRES) is a clinical/radiological syndrome characterized by symptoms that can include seizure, headache, impaired vision and hypertension, and can be confirmed by magnetic resonance imaging. Numerous reports have emerged that describe PRES in cancer patients. The list of me...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-014-0193-3
更新日期：2015-06-01 00:00:00
abstract：:Didemnin B is a depsipeptide derived from a Caribbean tunicate (sea squirt) that has demonstrated antineoplastic activity against a variety of murine tumor models, including the L1210 and P388 leukemia, the B16 melanoma, and M5076 sarcoma cell lines. Based on these data, we designed a phase II trial in which 15 patien...
journal_title：Investigational new drugs
pub_type： 临床试验,杂志文章
doi：10.1007/BF00877248
更新日期：1992-08-01 00:00:00
abstract：:Castrate-Resistant Prostate-Cancer (CRPC) is one of the most common malignancies occurring in men. Unfortunately, even if several recently approved agents clinically improved the outcome of CRPC patients, none of these is curative especially for a splice version of the Androgen Receptor (AR) AR-V7, which is a variant ...
journal_title：Investigational new drugs
pub_type： 杂志文章,评审
doi：10.1007/s10637-018-0653-2
更新日期：2018-12-01 00:00:00
abstract：:Degradation of basement membrane and extracellular matrix by matrix metalloproteinases (MMPs) is believed to be required for tumor invasion, tumor-induced angiogenesis and vascular invasion. A synthetic hydroxamate, batimastat (also known as BB-94), inhibits MMPs by binding the zinc ion in the active site of the MMP. ...
journal_title：Investigational new drugs
pub_type： 临床试验,杂志文章
doi：10.1007/BF00210790
更新日期：1996-01-01 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：:Twenty-four patients with acute leukemia or blast crisis (BC) of chronic myelocytic leukemia (CML) in relapse or refractory to standard chemotherapy, were eligible for treatment with mitoxantrone. Mitoxantrone (Novantrone; dihydroxyanthracenedione) was administered in a dose of 8-13 mg/m2 on five consecutive days. Fiv...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/BF00174171
更新日期：1985-01-01 00:00:00
abstract：:Studies with CGP 41 251 (I), an N-benzoylstaurosporine derivative and PKC-alpha inhibitor, revealed that oral administration of 400 microg/day of the compound to wild type mice on four successive days reversed multi drug resistance (Killion et al. Oncology Research 7: 453-459, 1995). In our study, the same regimen of ...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1023/a:1006260217400
更新日期：1999-01-01 00:00:00
abstract：:Purpose Anticancer agents are known to increase cancer-associated thrombosis (CAT) onset. CAT onset rate is reported to be 1.92% in cisplatin-based therapy, 6.1% in paclitaxel plus ramucirumab combination therapy, and 11.9% in bevacizumab monotherapy. Because immune checkpoint inhibitors (ICIs) cause a sudden increase...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-019-00881-6
更新日期：2020-08-01 00:00:00
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 erg...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-014-0168-4
更新日期：2015-02-01 00:00:00
abstract：:We have developed a specific and sensitive method aiming at docetaxel (Taxotere) determination in plasma of treated patients. This involved solid-phase extraction of 1 ml of plasma onto carboxylic acid (CBA) grafted silica cartridges followed by reversed-phase liquid chromatography with UV detection. The best selectiv...
journal_title：Investigational new drugs
pub_type： 临床试验,杂志文章
doi：10.1023/a:1006327302041
更新日期：1999-01-01 00:00:00
abstract：:Fifteen patients with advanced, cisplatin-refractory germ cell tumors (GCT) were treated on a phase II trial with topotecan. None of the 14 evaluable patients achieved a complete or partial response. Myelosuppression was the major toxicity. The median nadir leukocyte count was 1.75 cells/mm3, neutrophil count was 1.55...
journal_title：Investigational new drugs
pub_type： 临床试验,杂志文章
doi：10.1007/BF00872866
更新日期：1995-01-01 00:00:00
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：:Aberrant activation of the Wnt/β-catenin signaling pathway promotes osteosarcoma tumorigenesis and metastasis. In this study, we tested the hypothesis that osteosarcoma progression may be delayed by disrupting the Wnt/β-catenin pathway using small molecule inhibitors such as curcumin and PKF118-310. Effective inhibiti...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-009-9311-z
更新日期：2010-12-01 00:00:00
abstract：INTRODUCTION:Multidrug resistance in cancer represents a major problem in chemotherapy. The present study was designed to assess the cytotoxicity of anthraquinones from Pentas schimperi, namely damnacanthal (1), damnacanthol (2), 3-hydroxy-2-hydroxymethyl anthraquinone (3) and schimperiquinone B (4) against nine drug-s...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-015-0268-9
更新日期：2015-08-01 00:00:00
abstract：:XK469 (NSC 656889) is a water-soluble member of the novel quinoxaline family of antitumor agents. In vitro, XK469 demonstrated selective cytotoxicity for several murine solid tumors including colorectal and mammary adenocarcinoma cell lines, when compared to both leukemia and normal epithelial cells. In vivo, XK469 wa...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1023/a:1006206814025
更新日期：1998-01-01 00:00:00
abstract：BACKGROUND:Preclinical data suggested that sustained inhibition of the anabolic enzyme, ribonucleotide reductase (RR), by hydroxyurea (HU) may be critical for the anticancer effects of the drug. A phase I trial of continuous infusion HU with concomitant hyperfractionated, accelerated radiation therapy (CHU-CHRT) was in...
journal_title：Investigational new drugs
pub_type： 临床试验,杂志文章
doi：10.1023/a:1006102716920
更新日期：1998-01-01 00:00:00
abstract：:Indibulin is a synthetic small molecule which antitumor activity is based upon destabilization of microtubules. The primary study objectives were to determine the impact of fasted and fed condition on pharmacokinetic parameters, as well as the maximum tolerated dose of the oral drinking solution of indibulin administe...
journal_title：Investigational new drugs
pub_type： 杂志文章,多中心研究,随机对照试验
doi：10.1007/s10637-006-9027-2
更新日期：2007-06-01 00:00:00
abstract：BACKGROUND:TAS-102 is a nucleoside antitumor agent consisting of trifluridine (FTD) and tipiracil hydrochloride (TPI). We investigated the recommended dose (RD) of TAS-102 plus irinotecan for metastatic colorectal cancer refractory to 5-fluorouracil (5-FU) and oxaliplatin. METHODS:This study was used a escalated dose ...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-015-0271-1
更新日期：2015-10-01 00:00:00
abstract：:The modulation of intracellular nuclear factor-kappaB (NF-κB) signaling pathway involved in the deregulated expression of cell proliferation and cell cycle regulatory molecules is a pragmatic approach for chemoprevention. Eugenol (4-allyl-1-hydroxy-2-methoxybenzene), a natural phenolic constituent of oils of cloves is...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-009-9345-2
更新日期：2011-02-01 00:00:00
abstract：BACKGROUND:We performed a phase I study to determine the dose and safety of everolimus as a combination chemotherapy in peripheral T-cell lymphoma (PTCL). METHODS:Four dose levels (2.5 to 10 mg) of everolimus from days 1 to 14 with CHOP (750 mg/m(2) cyclophosphamide, 50 mg/m(2) doxorubicin, and 1.4 mg/m(2) (maximum 2 ...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-013-0015-z
更新日期：2013-12-01 00:00:00
abstract：:We performed a single-institution phase II study to evaluate the efficacy and toxicities of vinorelbine monotherapy in patients previously treated with anthracyclines and taxanes. Vinorelbine was administered at a dose level of 25 mg/m² intravenously on days 1, 8, 15 and 22, every four weeks, and responses were assess...
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
abstract：:Flavone acetic acid (FAA) was incubated for 1 to 48 hr with 3 established human colon cancer cell lines endowed with distinct degrees of phenotypic properties. All 3 lines responded to FAA in almost identical fashion; when incubated with the drug for only 1 hr, an initial decrease in survival was observed for concentr...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/BF00173501
更新日期：1986-01-01 00:00:00
abstract：:PA-U2, an engineered anthrax protective antigen that is activated by urokinase was combined with wildtype lethal factor in the treatment of Colo205 colon adenocarcinoma in vitro and B16-BL6 mouse melanoma in vitro and in vivo. This therapy was also tested in combination with the small molecule paclitaxel, based on pri...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-012-9847-1
更新日期：2013-02-01 00:00:00
abstract：:Compared to doxorubicin, equimolar epirubicin toxicity is reduced by about 50% by the epimerization of a hydrogen and hydroxyl group at the 4' position of the anthracycline sugar moiety. The circadian timing of doxorubicin administration markedly affects its lethal and sub-lethal bone marrow and gut toxicities in mice...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/BF00173645
更新日期：1988-12-01 00:00:00
