Abstract:
:Molecular profiling of markers involved in the activity of chemotherapeutic agents can shed light on the successes and failures of treatment in patients and can also provide a basis for individualization of therapy. Toward those ends, we have used reverse-phase protein lysate microarrays to evaluate expression of protein components of the nucleotide excision repair (NER) pathways. Those pathways strongly influence the anticancer activities of numerous drugs, including those that are the focus here, cisplatin and ecteinascidin 743 (Et-743; Yondelis, Trabectedin). Cisplatin is generally more active in cell types deficient in NER, whereas Et-743 tends to be less active in those cells. We measured protein expression and sensitivity to those drugs in 17 human ovarian and colon cancer cell lines (13 of them from the NCI-60 panel) and five xeroderma pigmentosum (XP) patient cell types, each containing a different NER defect. Of the NER proteins giving reliable signals, XPF and XPG showed the highest correlations of protein expression with drug activity across all three tissue-of-origin groups. When we compared protein expression data with mRNA expression data from Affymetrix U133A chips, we found no consistent correlation between the two across the cell lines studied, which reinforces the conclusion that protein measurements can give more interpretable mechanistic information than can transcript measurements. The work reported here provides motivation for larger proteomic studies with more cell types focused on potential biomarkers in additional pharmacologically pertinent pathways.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Stevens EV,Nishizuka S,Antony S,Reimers M,Varma S,Young L,Munson PJ,Weinstein JN,Kohn EC,Pommier Ydoi
10.1158/1535-7163.MCT-07-0192subject
Has Abstractpub_date
2008-01-01 00:00:00pages
10-8issue
1eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-07-0192journal_volume
7pub_type
杂志文章abstract::The protein kinase family represents an enormous opportunity for drug development. However, the current limitation in structural diversity of kinase inhibitors has complicated efforts to identify effective treatments of diseases that involve protein kinase signaling pathways. We have identified a new structural class ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2004-01-01 00:00:00
abstract::Resistance to radiotherapy due to insufficient cancer cell death is a significant cause of treatment failure in non-small cell lung cancer (NSCLC). The endogenous caspase-8 inhibitor FLIP is a critical regulator of cell death that is frequently overexpressed in NSCLC and is an established inhibitor of apoptotic cell d...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-16-0211
更新日期:2016-10-01 00:00:00
abstract::Cells contain a large number of antioxidants to prevent or repair the damage caused by reactive oxygen species. One component of the antioxidant system, manganese superoxide dismutase (MnSOD), is localized in the mitochondria, and the levels of this protein have been previously shown to inversely correlate with pancre...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2003-04-01 00:00:00
abstract::Many genes, with products involved in the protection of cells against carcinogens, oxidants, and other toxic chemicals, are under the transcriptional control of a simple DNA regulatory element [i.e., the antioxidant response element (ARE)]. One or more functional AREs have been confirmed or are believed to exist in th...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章,评审
doi:
更新日期:2004-07-01 00:00:00
abstract::ABT-263 is a potent, orally bioavailable inhibitor of the antiapoptotic Bcl-2 family members Bcl-2, Bcl-x(L), and Bcl-w, which is currently in phase I clinical trials. Previous work has shown that this compound has low nanomolar cell-killing activity in a variety of lymphoma and leukemia cell lines, many of which over...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-08-0268
更新日期:2008-10-01 00:00:00
abstract::The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that exists in two complexes (mTORC1 and mTORC2) and integrates extracellular and intracellular signals to act as a master regulator of cell growth, survival, and metabolism. The PI3K/AKT/mTOR prosurvival pathway is often dysregulated in mul...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-14-0711
更新日期:2015-02-01 00:00:00
abstract::Melanoma is a highly metastatic and deadly disease. An agent simultaneously targeting the COX-2, PI3K/Akt, and mitogen-activated protein kinase (MAPK) signaling pathways that are deregulated in up to 70% of sporadic melanomas might be an effective treatment, but no agent of this type exists. To develop a single drug i...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-12-0492
更新日期:2013-01-01 00:00:00
abstract::Replication protein A (RPA) is a single-strand DNA-binding protein with essential roles in DNA replication, recombination, and repair. It is necessary for the formation of the preincision complex that is required for proper incision of damaged DNA nucleotides during DNA repair. We have previously identified small mole...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-11-0303
更新日期:2011-10-01 00:00:00
abstract::Mithramycin A is a DNA-binding antitumor agent, which has been clinically used in the therapies of several types of cancer and Paget's disease. In this study, we investigated the combined effect of mithramycin A and tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) on apoptosis of cancer cells. In ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-06-0426
更新日期:2006-11-01 00:00:00
abstract::Survivin, an inhibitor of apoptosis protein, is highly expressed in most cancers and associated with chemotherapy resistance, increased tumor recurrence, and shorter patient survival, making antisurvivin therapy an attractive cancer treatment strategy. However, growing evidence indicates that survivin is expressed in ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章,评审
doi:10.1158/1535-7163.MCT-05-0375
更新日期:2006-05-01 00:00:00
abstract::Recently there have been explosive discoveries of new long noncoding RNAs (lncRNA) obtained by progress in the technology of second-generation sequencing. Genome scale analysis of transcriptome, in conjunction with studies on chromatin modifications at the epigenetic level, identified lncRNAs as a novel type of noncod...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章,评审
doi:10.1158/1535-7163.MCT-18-0124
更新日期:2018-09-01 00:00:00
abstract::The challenge of developing effective pharmacodynamic biomarkers for preclinical and clinical testing of FGFR signaling inhibition is significant. Assays that rely on the measurement of phospho-protein epitopes can be limited by the availability of effective antibody detection reagents. Transcript profiling enables ac...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-16-0297
更新日期:2016-11-01 00:00:00
abstract::The oncoprotein Eps8 facilitates proliferation in fibroblasts and colon cancer cells. However, its role in human cervical cancer is unclear. By immunohistochemical staining and Western blotting, aberrant Eps8 expression was observed in cervical carcinoma compared with normal cervical epithelial cells. Clinicopathologi...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-07-2388
更新日期:2008-06-01 00:00:00
abstract::Imatinib mesylate has shown remarkable efficacy in the treatment of patients in the chronic phase of chronic myeloid leukemia. However, despite an overall significant hematological and cytogenetic response, imatinib therapy may favor the emergence of drug-resistant clones, ultimately leading to relapse. Some imatinib ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-10-0979
更新日期:2011-05-01 00:00:00
abstract::Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy with one of the worst outcomes among all cancers. PDA often recurs after initial treatment to result in patient death despite the use of chemotherapy or radiation therapy. PDA contains a subset of tumor-initiating cells capable of extensive self-renewa...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-10-0370
更新日期:2010-09-01 00:00:00
abstract::The number of approved antiangiogenic drugs is constantly growing and emphasizes the need for predictive biomarkers. The aim of this study was to analyze the predictive value of epidermal growth factor-like domain 7 (EGFL7) and microRNA-126 (miR126) to first-line chemotherapy combined with bevacizumab, in patients wit...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章,随机对照试验
doi:10.1158/1535-7163.MCT-14-0131
更新日期:2014-09-01 00:00:00
abstract::Synthetic retinoid-related molecules (RRMs) have been described that show strong antiproliferative activity and induce apoptosis in cancer cells. These RRMs induce caspase activity independently of the retinoid receptors in Jurkat T cells. We observed that the inhibitor of cathepsins B and L Z-FA-fmk blocks the induct...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2003-03-01 00:00:00
abstract::Met-amplified EGFR-tyrosine kinase inhibitor (TKI)-resistant non-small cell lung cancer (NSCLC) harboring an activating EGFR mutation is responsive to concurrent EGFR-TKI and Met-TKI treatment in a preclinical model. Here, we determined that Met-amplified gefitinib-resistant cells acquire dual resistance to inhibition...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-16-0313
更新日期:2016-12-01 00:00:00
abstract::Neuroblastoma is the most common extracranial solid tumor of childhood. The activity of J1 (l-melphalanyl-p-l-fluorophenylalanine ethyl ester), an enzymatically activated melphalan prodrug, was evaluated in neuroblastoma models in vitro and in vivo. Seven neuroblastoma cell lines with various levels of drug resistance...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-07-0156
更新日期:2007-09-01 00:00:00
abstract::Farnesyl transferase inhibitors (FTI) exhibit anticancer activity as a single agent in preclinical studies and show promise in combination with other therapeutics in clinical trials. Previous studies show that FTIs arrest cancer cells in mitosis; however, the mechanism by which this occurs is unclear. Here, we observe...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章,随机对照试验
doi:10.1158/1535-7163.MCT-06-0703
更新日期:2007-04-01 00:00:00
abstract::There is considerable interest in the clinical development of inhibitors of mTOR complexes mTORC1 and 2. Because mTORC1 and its downstream mRNA translation effectors may protect against genotoxic DNA damage, we investigated the inhibition of mTORC1 and mTORC1/2 in the ability to reverse platinum resistance in tissue c...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-15-0926
更新日期:2016-07-01 00:00:00
abstract::The camptothecin derivatives topoisomerase I (TOP1) inhibitors, irinotecan and topotecan, are FDA approved for the treatment of colorectal, ovarian, lung and breast cancers. Because of the chemical instability of camptothecins, short plasma half-life, drug efflux by the multidrug-resistance ABC transporters, and the s...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-19-1064
更新日期:2020-08-01 00:00:00
abstract::With current techniques, it remains a challenge to assess coregulator binding of nuclear receptors, for example, the estrogen receptor alpha (ERα). ERα is critical in many breast tumors and is inhibited by antiestrogens such as tamoxifen in cancer therapy. ERα is also modified by acetylation and phosphorylation that a...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-11-0855
更新日期:2012-04-01 00:00:00
abstract::Radiotherapy can be synergistically combined with immunotherapy in mouse models, extending its efficacious effects outside of the irradiated field (abscopal effects). We previously reported that a regimen encompassing local radiotherapy in combination with anti-CD137 plus anti-PD-1 mAbs achieves potent abscopal effect...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-18-0558
更新日期:2019-03-01 00:00:00
abstract::Leukemia cells escape BCR-ABL-targeted therapy by developing mutations, such as T315I, in the p210(BCR-ABL) fusion protein in Philadelphia chromosome-positive chronic myeloid leukemia (CML). Although most effort has been focused on development of new tyrosine kinase inhibitors, enrichment of these small-molecule inhib...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-15-0577-T
更新日期:2016-05-01 00:00:00
abstract::High Mycoplasma infection in gastric cancer tissues suggests a possible association between Mycoplasma infection and tumorigenesis. By using human gastric cancer cells AGS and mouse melanoma cells B16F10 stably expressing p37, the major immunogen of Mycoplasma hyorhinis, we found that p37 enhanced cell motility, migra...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-07-2191
更新日期:2008-03-01 00:00:00
abstract::Raf inhibitors are under clinical investigation, specifically in patients with tumor types harboring frequent activating mutations in B-Raf. Here, we show that cell lines and tumors harboring mutant B-Raf were sensitive to a novel series of Raf inhibitors (e.g., (V600E)B-Raf A375, IC(50) on cells = 2 nmol/L; ED(50) on...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-10-0181
更新日期:2010-08-01 00:00:00
abstract::Bone metastases occur in more than one-third of patients with advanced lung cancer and are difficult to treat. We showed previously the therapeutic effect of a third-generation bisphosphonate, minodronate, and anti-parathyroid hormone-related protein (PTHrP) neutralizing antibody on bone metastases induced by the huma...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-08-0874
更新日期:2009-01-01 00:00:00
abstract::Small cell lung cancer (SCLC) easily acquires multidrug resistance after successful initial therapy. Overexpression of ATP-binding cassette (ABC) transporters is important for the multidrug resistance. Among them, ABCB1 and ABCG2 are known to be upregulated in chemoresistant SCLC cells. We found that human epidermal g...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-11-0884
更新日期:2012-04-01 00:00:00
abstract::The oncogenic beta-catenin/T-cell factor (TCF) signal is a common trigger inducing expressions of various cancer-related genes and is activated in various types of human malignancy. The aim of this study was to create an effective double-stranded DNA decoy that would interfere with endogenous TCF hyperactivity in tumo...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-05-0388
更新日期:2006-04-01 00:00:00