Abstract:
:Bortezomib combination with gemcitabine/cisplatin in patients with advanced tumors, predominantly non-small cell lung cancer (NSCLC), showed an unexpected transient drop in the deoxycytidine plasma levels, a marker for gemcitabine activity. This study investigates the pharmacokinetic/pharmacodynamic effect of bortezomib on gemcitabine in NSCLC and peripheral blood mononuclear cells (PBMC). Gemcitabine metabolites, including difluoro-dCTP (dFdCTP), were studied in PBMCs from bortezomib/gemcitabine/cisplatin-treated patients and from volunteers and NSCLC cells (H460 and SW1573) exposed to 4 h simultaneous or sequential treatments of gemcitabine (50 μmol/L, 4 h) and bortezomib (100 nmol/L, 2 h). Gemcitabine total phosphate levels measured by liquid chromatography-tandem mass spectrometry in PBMCs from bortezomib/gemcitabine/cisplatin-treated patients were strongly reduced after 90 min (-82.2%) up to 4 h post-gemcitabine infusion compared with gemcitabine/cisplatin-treated patients. Accordingly, bortezomib/gemcitabine combinations reduced dFdCTP in PBMCs treated ex vivo. Surprisingly, differential effects were observed in NSCLC cells. dFdCTP decreased after 4 h following gemcitabine removal in H460 but continued to increase for 24 h in SW1573. However, dFdCTP significantly increased (2-fold) in both cell lines in the bortezomib → gemcitabine exposure, coinciding with a major reduction in cell growth compared with single drugs, and the highest increase of deoxycytidine kinase expression, possibly mediated via E2F-1. Bortezomib affects differently gemcitabine pharmacokinetics/pharmacodynamics in PBMCs and NSCLC cells, suggesting that PBMCs are not adequate to evaluate the anticancer activity of bortezomib/gemcitabine combinations. The bortezomib → gemcitabine/cisplatin schedule appeared a safe and active combination for the treatment of advanced NSCLC and the bortezomib → gemcitabine was the most cytotoxic combination in NSCLC cells. The increase of deoxycytidine kinase and dFdCTP might contribute to this synergistic interaction and supports its further clinical investigation.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Ceresa C,Giovannetti E,Voortman J,Laan AC,Honeywell R,Giaccone G,Peters GJdoi
10.1158/1535-7163.MCT-08-0700subject
Has Abstractpub_date
2009-05-01 00:00:00pages
1026-36issue
5eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-08-0700journal_volume
8pub_type
杂志文章abstract::Vascular endothelial growth factor (VEGF) is a primary stimulant of angiogenesis and is a macrophage chemotactic protein. Inhibition of VEGF is beneficial in combination with chemotherapy for some breast cancer patients. However, the mechanism by which inhibition of VEGF affects tumor growth seems to involve more than...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-09-0280
更新日期:2009-07-01 00:00:00
abstract::HA14-1 is a small molecular compound that was identified based on the structure of Bcl-2. HA14-1 interacts with Bcl-2 and inhibits the antiapoptotic effect of Bcl-2. We investigated the mechanism of HA14-1-induced apoptosis and found that HA14-1 induces translocation of Bax from cytosols to the mitochondria. Cells def...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2002-10-01 00:00:00
abstract::Signaling from the human hematopoietic stem cell (HSC) niche formed by osteoblastic cells regulates hematopoiesis. We previously found that retinoic acid receptor alpha (RARα), a transcription factor activated by retinoic acid (RA), mediates both granulocytic and osteoblastic differentiation. This effect depends on de...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-11-0584
更新日期:2012-02-01 00:00:00
abstract::Aberrant DNA methylation patterns play an important role in the pathogenesis of hematologic malignancies. The DNA methyltransferase inhibitors azacytidine and decitabine have shown significant clinical benefits in the treatment of myelodysplastic syndrome (MDS), but their precise mode of action remains to be establish...
journal_title:Molecular cancer therapeutics
pub_type: 临床试验,杂志文章
doi:10.1158/1535-7163.MCT-08-0411
更新日期:2008-09-01 00:00:00
abstract::5'-Fluorouracil (5-FU), used in the treatment of colon and breast cancers, is converted intracellularly to 5'-fluoro-2'-deoxyuridine (5-FUdR) by thymidine phosphorylase and is subsequently phosphorylated by thymidine kinase to 5'-fluoro-2'-dUMP (5-FdUMP). This active metabolite, along with the reduced folate cofactor,...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-04-0291
更新日期:2005-05-01 00:00:00
abstract::The humanized anti-HER2 monoclonal antibody (mAb) trastuzumab (Herceptin; Genentech) effectively inhibits human epidermal growth factor receptor 2 (HER2)-positive breast tumors. However, many patients responding to treatment often develop resistance. Cross-talk between type I insulin-like growth factor receptor (IGF-I...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-13-0558
更新日期:2014-01-01 00:00:00
abstract::This work is based on previous evidence showing that chemotactic sequence of the urokinase receptor (uPAR(88-92)) drives angiogenesis in vitro and in vivo in a protease-independent manner, and that the peptide Ac-Arg-Glu-Arg-Phe-NH(2) (RERF) prevents both uPAR(88-92)- and VEGF-induced angiogenesis. New N-acetylated an...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-13-0949
更新日期:2014-05-01 00:00:00
abstract::Ras signaling can be modulated by the scaffolding activity of kinase suppressor of Ras-1 (KSR-1) and by the hKSR-2 protein, resulting in diverse phenotypic outcomes. The mitogen-activated protein kinase cascade downstream from Ras and KSRs includes Raf-1 and extracellular signal-regulated kinase 1/2 kinases, known to ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-08-0276
更新日期:2008-09-01 00:00:00
abstract::Members of the signal transducer and activator of transcription (STAT) family of transcription factors are potential targets for the treatment and prevention of cancers including non-small-cell lung cancer. STAT proteins can be phosphorylated and activated by diverse upstream kinases including cytokine receptors and t...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-10-0502
更新日期:2011-03-01 00:00:00
abstract::The FGF receptors (FGFR) are tyrosine kinases that are constitutively activated in a subset of tumors by genetic alterations such as gene amplifications, point mutations, or chromosomal translocations/rearrangements. Recently, small-molecule inhibitors that can inhibit the FGFR family as well as the VEGF receptor (VEG...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-14-0248
更新日期:2014-11-01 00:00:00
abstract::Molecular mechanisms underlying epothilone-induced apoptotic cell death were investigated in SW620 human colon cancer cells. Treatment with epothilone B and D at different concentrations (1-100 nmol/L) dose-dependently inhibited cell growth and caused cell cycle arrest at G2-M, which was followed by apoptosis. Consist...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-07-0002
更新日期:2007-10-01 00:00:00
abstract::The emergence of drug resistance is often an inevitable obstacle that limits the long-term effectiveness of clinical cancer chemotherapeutics. Although various forms of cancer cell-intrinsic mechanisms of drug resistance have been experimentally revealed, the role and the underlying mechanism of tumor microenvironment...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-17-0634
更新日期:2018-04-01 00:00:00
abstract::Epithelial ovarian cancer is characterized by a low recovery rate because the disease is typically diagnosed at an advanced stage, by which time most patients (80%) already exhibit disseminated neoplasia. The cytokine receptor CXCR4 has been implicated in the development of metastasis in various tumor types. Using a p...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-17-0643
更新日期:2018-02-01 00:00:00
abstract::Molecular characterization of radical prostatectomy specimens after systemic therapy may identify a gene expression profile for resistance to therapy. This study assessed tumor cells from patients with prostate cancer participating in a phase II neoadjuvant docetaxel and androgen deprivation trial to identify mediator...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-13-0775
更新日期:2014-05-01 00:00:00
abstract::Protein tyrosine kinases of the Janus kinase (JAK) family are associated with many cytokine receptors, which, on ligand binding, regulate important cellular functions such as proliferation, survival, and differentiation. In multiple myeloma, JAKs may be persistently activated due to a constant stimulation by interleuk...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-08-0149
更新日期:2009-01-01 00:00:00
abstract::Invasive ductal carcinomas (IDC) of the breast are associated with altered expression of hormone receptors (HR), amplification or overexpression of HER2, or a triple-negative phenotype. The most aggressive cases of IDC are characterized by a high proliferation rate, a great propensity to metastasize, and their ability...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-14-0945
更新日期:2015-06-01 00:00:00
abstract::The breast-specific antigen alpha-lactalbumin is expressed in >60% of breast cancer tissues. To evaluate the effect of gene therapy for breast cancer by controlling adenovirus replication with human alpha-lactalbumin promoter, we investigated the activity of a 762-bp human alpha-lactalbumin promoter. Alpha-lactalbumin...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-05-0167
更新日期:2005-12-01 00:00:00
abstract::STAT3 is an important transcriptional factor for cell growth, differentiation, and apoptosis. Although evidence suggests a positive role for STAT3 in cancer, the inhibitory effects of tumor STAT3 on natural killer (NK) cell functions in human hepatocellular carcinoma are unclear. In this study, we found that blocking ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-12-1087
更新日期:2013-12-01 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::Aptamers, also termed as decoys or "chemical antibodies," represent an emerging class of therapeutics. They are short DNA or RNA oligonucleotides or peptides that assume a specific and stable three-dimensional shape in vivo, thereby providing specific tight binding to protein targets. In some cases and as opposed to a...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章,评审
doi:10.1158/1535-7163.MCT-06-0172
更新日期:2006-12-01 00:00:00
abstract::The NF-κB transcription factor functions as a crucial regulator of cell survival and chemoresistance in pancreatic cancer. Recent studies suggest that tocotrienols, which are the unsaturated forms of vitamin E, are a promising class of anticancer compounds that inhibit the growth and survival of many cancer cells, inc...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-11-0424
更新日期:2011-12-01 00:00:00
abstract::Complexities in treating breast cancer with bone metastasis are enhanced by a vicious protumorigenic pathology, involving a shift in skeletal homeostasis toward aggressive osteoclast activity and polarization of immune cells supporting tumor growth and immunosuppression. Recent studies signify the role of receptor act...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-20-0378
更新日期:2020-12-01 00:00:00
abstract::Small cell lung cancer (SCLC) has a poor prognosis. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase regulating cell proliferation, survival, migration, and invasion, which is overexpressed and/or activated in several cancers, including SCLC. We wanted to determine whether FAK contributes to SCLC aggressi...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-18-0328
更新日期:2019-01-01 00:00:00
abstract::The functional and therapeutic importance of the Warburg effect is increasingly recognized, and glycolysis has become a target of anticancer strategies. We recently reported the identification of a group of novel small compounds that inhibit basal glucose transport and reduce cancer cell growth by a glucose deprivatio...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-12-0131
更新日期:2012-08-01 00:00:00
abstract::Measles viruses (MV) are rapidly inactivated by anti-measles neutralizing antibodies, which has limited their clinical performance as oncolytic agents. Here, by substituting the H and F surface glycoproteins of MV with those from the homologous canine distemper virus (CDV) and engineering the CDV H attachment protein ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-20-0134
更新日期:2020-10-01 00:00:00
abstract::In breast and certain other cancers, receptor tyrosine kinases, including the insulin-like growth factor I receptor (IGF-IR), play an important role in promoting the oncogenic process. The IGF-IR is therefore an important target for developing new anti-breast cancer therapies. An initial screening of a chemical librar...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-05-0397
更新日期:2006-04-01 00:00:00
abstract::This meeting report on the fourth Fabisch Symposium for Cancer Research and Molecular Biology describes the aims of the international meeting, the main topics of the presentations, and the highlights of the conference. The fourth Fabisch Symposium was the second on Targeted Tumor Therapies and held from April 1-3, 200...
journal_title:Molecular cancer therapeutics
pub_type:
doi:10.1158/1535-7163.MCT-09-0491
更新日期:2010-01-01 00:00:00
abstract::HER2-targeted therapies, such as trastuzumab, have increased the survival rates of HER2+ breast cancer patients. However, despite these therapies, many tumors eventually develop resistance to these therapies. Our lab previously reported an unexpected sensitivity of HER2+ breast cancer cells to poly (ADP-ribose) polyme...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-17-0302
更新日期:2018-05-01 00:00:00
abstract::Repurposing cationic amphiphilic drugs (CAD) for cancer treatment is emerging as an attractive means to enhance the efficacy of chemotherapy. Many commonly used CADs, including several cation amphiphilic antihistamines and antidepressants, induce cancer-specific, lysosome-dependent cell death and sensitize cancer cell...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-18-1406
更新日期:2019-09-01 00:00:00
abstract::Urokinase plasminogen activator (uPA) is a tumor-specific protease highly expressed in several types of solid tumors and rarely present on normal cells under physiologic conditions. Due to its high expression on metastatic tumors, several different strategies have been used to target the urokinase system. These have m...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-06-0315
更新日期:2006-10-01 00:00:00