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 their ability to inhibit the activity of the isolated enzymes. A dose- and time-response for induction of cell death was demonstrated for each compound. A proteomic study showed that inhibitor treatment caused an increase of markers of cell stress, including induction of levels of the autophagy marker, LC-3-II. Levels of this marker protein were highest at cytotoxic inhibitor concentrations, implicating autophagy in the cell death process. An in vivo mouse model showed that one of these inhibitors markedly impaired tumor growth. It is concluded that development of drugs to target these two proteases may provide a novel approach to treating neuroblastoma.
journal_name
Invest New Drugsjournal_title
Investigational new drugsauthors
Cartledge DM,Colella R,Glazewski L,Lu G,Mason RWdoi
10.1007/s10637-012-9826-6subject
Has Abstractpub_date
2013-02-01 00:00:00pages
20-9issue
1eissn
0167-6997issn
1573-0646journal_volume
31pub_type
杂志文章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::A retrospective cohort study was performed to investigate the effectiveness of preemptive postsurgical therapy with cetuximab for patients with a major risk of recurrence or metastasis after clinical complete resection of primary oral squamous cell carcinoma (OSCC). The study period was from 2007 to 2019 for patients ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-021-01062-0
更新日期:2021-01-15 00:00:00
abstract::Angiogenesis is recognized as an important biological process that allows growth of a tumor beyond an initial small size. PTK787/ZK222584, a potent orally active angiogenesis inhibitor capable of inhibiting all known isoforms of Vascular Endothelial Growth Factor (VEGF) receptor, belongs to the class of aminophthalazi...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-008-9157-9
更新日期:2009-02-01 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
abstract::Chemoprevention opens new perspectives in the prevention of cancer and other degenerative diseases. Use of target-organ biological models at the histological and genetic levels can markedly facilitate the identification of potential chemopreventive agents. Our aim was to study the chemopreventive efficacy of pronyl-ly...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-008-9122-7
更新日期:2008-12-01 00:00:00
abstract::Advances in the understanding of the molecular basis for acute myeloid leukemia (AML) have generated new potential targets for treatment. Fms-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in AML and mutations in this gene are associated with poor overall survival. AXL plays a role in the ac...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-017-0470-z
更新日期:2017-10-01 00:00:00
abstract:INTRODUCTION:For decades, determination of the recommended Phase 2 dose (RP2D) was based on the toxicity (especially the maximum tolerated dose or MTD) experienced by patients enrolled in dose-escalating Phase 1 trials investigating anti-cancer agents. Recent studies suggest that this toxicity-based strategy is not sui...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-010-9574-4
更新日期:2012-04-01 00:00:00
abstract:PURPOSE:This study investigated the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetic (PK) profiles of DHP107, a novel oral paclitaxel containing neither Cremophor EL nor P-glycoprotein (P-gp) inhibitor. PATIENTS AND METHODS:Patients with advanced solid tumors refractory to all standard t...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-012-9841-7
更新日期:2013-06-01 00:00:00
abstract::A series of 96 diarylamidine (and diarylimidazoline) derivatives were evaluated for their inhibitory effects on the growth and DNA synthesis of murine leukemia L1210 cells. The amidino- and imidazolino-substituted aryl moieties of the compounds consisted of phenyl, indole, indene, benzofuran, benzo[b]thiophene or benz...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00172069
更新日期:1983-01-01 00:00:00
abstract::The aim of this study was to determine the antitumor activity of irofulven when administered in combination with a variety of antimitotic agents. Irofulven in combination with either paclitaxel or docetaxel demonstrated synergistic activity in both the in vitro and in vivo studies. The majority of xenograft bearing an...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1023/a:1016201807796
更新日期:2002-08-01 00:00:00
abstract::In this multi-institutional phase II study, VM-26 or Teniposide was administered to forty-two patients with advanced colorectal cancer. Patients were initially treated at 60 mg/M2 daily for 5 days with dose adjustments depending on toxicity. One complete response and one partial response were observed lasting six and ...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1007/BF00216931
更新日期:1990-02-01 00:00:00
abstract::Imidazolium-trans-dimethylsulfoxideimidazoletetrachlororuthenate (NAMI-A) is a ruthenium compound effective on solid tumor metastases. In this study, we evaluated the effects of different routes of administration of NAMI-A on the distribution to primary tumor, lungs and kidneys in BD2F1 hybrids with Lewis lung carcino...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1023/a:1022916310694
更新日期:2003-02-01 00:00:00
abstract::The effect of the single-chain alkylphospholipid perifosine was analyzed in p53(wild-type) (SKW6.4, OCI and MOLM), p53(mutated) (BJAB, MAVER) and p53(null) (HL-60) leukemic cell lines. Perifosine promoted cytotoxicity with a combination of apoptosis induction in all cell lines and cell cycle block at the G(2)M checkpo...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-009-9370-1
更新日期:2011-04-01 00:00:00
abstract::Withaferin A (WA), a steroidal lactone derived from the plant Vassobia breviflora, has been reported to have anti-proliferative, pro-apoptotic, and anti-angiogenic properties against cancer growth. In this study, we identified several key underlying mechanisms of anticancer action of WA in glioblastoma cells. WA was f...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-012-9888-5
更新日期:2013-06-01 00:00:00
abstract::Background To determine the recommended dose (RD) of a combination of PM01183 and gemcitabine in patients with advanced solid tumors. Methods Forty-five patients received escalating doses of PM01183/gemcitabine on Days 1 and 8 every 3 weeks (d1,8 q3wk) following a standard 3 + 3 design. Results PM01183 3.5 mg flat dos...
journal_title:Investigational new drugs
pub_type: 杂志文章,多中心研究
doi:10.1007/s10637-016-0410-3
更新日期:2017-04-01 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::P-cadherin is frequently up-regulated in solid tumors such as gastric, colon, lung, pancreatic and breast cancers. Although P-cadherin promotes cadherin-mediated cell adhesion, the gastric cancer-linked regulation of P-cadherin has not been extensively investigated. In this study, we found epigenetic regulation of P-c...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-011-9710-9
更新日期:2012-08-01 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
abstract::In an on-going Phase II evaluation, dianhydrogalactitol (NSC 132313) was administered intravenously to 28 patients with advanced or recurrent non-squamous cell carcinoma of the cervix. The initial dosage was 60 mg/m2/wk with escalation to 75 mg/m2/wk if there were no adverse effects. Twenty-seven patients were evaluab...
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::Osimertinib is a molecularly targeted agent used to treat non-small cell lung cancer (NSCLC) patients with an epidermal growth factor receptor (EGFR) T790M mutation. However, its efficacy and safety profile when patients have poor performance status (PS) is unknown. Therefore, we conducted an open-label, multi-center,...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-020-00943-0
更新日期:2020-12-01 00:00:00
abstract:PURPOSE:This phase I study aims at assessing the safety and tolerability of LY2603618, a selective inhibitor of Checkpoint Kinase 1, in combination with pemetrexed and determining the maximum tolerable dose and the pharmacokinetic parameters. EXPERIMENTAL DESIGN:This was an open-label, multicenter, dose-escalation stu...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-012-9815-9
更新日期:2013-02-01 00:00:00
abstract:PURPOSE:The transcription factor nuclear factor-kB (NFkB) is implicated in gastric cancer carcinogenesis and survival, and its inhibition by proteosome inhibition is associated with preclinical gastric cancer anti-tumor activity. We examined the single agent efficacy of bortezomib, a selective proteasome inhibitor, in ...
journal_title:Investigational new drugs
pub_type: 杂志文章,多中心研究
doi:10.1007/s10637-010-9474-7
更新日期:2011-12-01 00:00:00
abstract::alpha-Difluoromethylornithine (DFMO) is a known irreversible inhibitor of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis. Cyclosporine (CsA) has been reported to inhibit ODC activity in vitro. In the present study, we compared the effects of DFMO and CsA on growth, survival, and poly...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00175295
更新日期:1987-01-01 00:00:00
abstract::Breast cancer is commonly treated with anti-estrogens or aromatase inhibitors, but resistant disease eventually develops and new therapies for such resistance are of great interest. We have previously isolated several tamoxifen-resistant variant sub-lines of the MCF-7 breast cancer cell line and provided evidence that...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-011-9768-4
更新日期:2012-12-01 00:00:00
abstract:PURPOSE:ZD0473 (AMD473) [cis-amminedichloro(2-methylpyridine) platinum(II)] is a novel platinum agent of proven activity in vitro against a variety of human tumor-derived cell lines even with intrinsic or acquired resistance to CDDP. The aim of this study is to provide the basis for a rational design of ZD0473-based co...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1023/B:DRUG.0000036682.99818.71
更新日期:2004-11-01 00:00:00
abstract::Drug lag, which delays patients' access to medicinal products, is typically associated with pharmaceutical regulations. To shorten drug lag, health authorities may establish new policies to liberalize the regulations, a step that is important in countries, such as Taiwan, with consumer demand for imported novel therap...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-018-00715-x
更新日期:2019-10-01 00:00:00
abstract::A new anthracycline derivative, SM5887, in combination with commonly used anticancer agents was evaluated against T-cell leukemia MOLT-3 and human osteosarcoma MG-63 cell lines in culture. MOLT-3 and MG-63 cells were incubated with various concentrations of 13-hydroxy SM5887 (SM5887-OH, the active metabolite of SM5887...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00180811
更新日期:1996-01-01 00:00:00
abstract::An automated in vitro technique for drug toxicity testing is described. Human tumor cells were cultured for 2 days in 96-well microtiter plates before the addition of serial dilutions of drugs. At day 5 the cultures were terminated by the addition of a solution containing propidium iodide, ink and triton X-100 (PIT). ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00203541
更新日期:1987-01-01 00:00:00
abstract:BACKGROUND:To evaluate the safety and tolerability of two different weekly doses of the fully humanized epidermal growth factor receptor (EGFR)-targeting monoclonal antibody matuzumab combined with high-dose 5-fluorouracil, leucovorin and cisplatin (PLF) in the first-line treatment of patients with EGFR-positive advanc...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-012-9848-0
更新日期:2013-06-01 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