Peptide-displayed phage libraries are billion-clone collections of diverse chimeric bacteriophage particles, decorated by genetically fused peptides built from a random combination of natural amino acids. Studying the molecular evolution of peptide-displayed libraries in mammalian model systems, using in vivo phage display techniques, can provide invaluable knowledge about the underlying physiology of the vasculature system, allow recognition of organ- and tissue-specific networks of protein-protein interactions, and provide ligands for targeted diagnostics and therapeutics. Recently, we discovered that landscape phage libraries, a specific type of multivalent peptide phage display library, expose on their surface comprehensive collections of elementary binding units (EBUs), which can form short linear motifs (SLiMs) that interact with functional domains of physiologically relevant proteins.
View Article and Find Full Text PDF5-aza-2′,2′-difluorodeoxycytidine (NUC013) has been shown to be significantly safer and more effective than decitabine in xenograft models of human leukemia and colon cancer. However, it suffers from a similar short half-life as other DNA methyltransferase inhibitors with a 5-azacytosine base, which is problematic for nucleosides that primarily target tumor cells in S phase. Because of the relative instability of 5-azanucleosides, a prodrug approach was developed to improve the pharmacology of NUC013.
View Article and Find Full Text PDFVitamin E phosphate (VEP) nucleoside prodrugs are designed to bypass two mechanisms of tumor resistance to therapeutic nucleosides: nucleoside transport and kinase downregulation. Certain isoforms of vitamin E (VE) have shown activity against solid and hematologic tumors and result in chemosensitization. Because gemcitabine is one of the most common chemotherapeutics for the treatment of cancer, it was used to demonstrate the constructs utility.
View Article and Find Full Text PDFIn this letter we report first nonpeptide inhibitors of hepatocyte growth factor (HGF) activation. These compounds inhibit the three proteases (matriptase, hepsin, and HGF activator) required for HGF maturation. We show that 6, 8a, 8b, and 8d block activation of fibroblast-derived pro-HGF, thus preventing fibroblast-induced scattering of DU145 prostate cancer cells.
View Article and Find Full Text PDFRadiother Oncol
September 2013
Purpose: Activation of the DNA damage responsive protein kinase ATM is a critical step for cellular survival in response to ionizing irradiation (IR). Direct targets of ATM regulating radiosensitivity remain to be fully investigated. We have recently reported that ATM phosphorylates the transcriptional repressor Snail on Serine 100.
View Article and Find Full Text PDFNucleosides Nucleotides Nucleic Acids
January 2013
Clofarabine, an approved anticancer drug, was evaluated in combination with radiation in six subcutaneously implanted human tumor xenograft models. Clofarabine had no effect on the growth of SF-295 glioblastoma, which was not enhanced by radiation. There was no difference between clofarabine with and without radiation in the DU-145 prostate model.
View Article and Find Full Text PDFInt J Radiat Oncol Biol Phys
January 2008
Purpose: Combination treatment with radiotherapy and chemotherapy has emerged as the dominant form of cancer adjuvant regimens in recent years. Clofarabine, a newly approved drug for pediatric leukemia, is a second-generation purine nucleoside analogue that can block DNA synthesis and inhibit DNA repair. Therefore, we hypothesized that clofarabine could work synergistically with radiotherapy to increase the tumor cell response.
View Article and Find Full Text PDFPurpose: We explore the utility of the adenovirus-mediated delivery of proapoptotic Bax for enhancing the cytotoxicity of radiotherapy (RT) in RT-refractory glioma cells.
Materials And Methods: Cell lines D54 MG and U87 MG (p53 wild-type), and U251 MG and U373 MG (p53 mutant), and patient-derived astrocytes were evaluated. Cells were irradiated and infected with an inducible adenovirus encoding Bax.
Purpose: To investigate treatment of human pancreatic cancer cell lines and xenografts with combinations of Erbitux (IMC-C225) anti-epidermal growth factor receptor (EGFR) antibody, gemcitabine, and radiation.
Methods And Materials: BxPC-3 and MiaPaCa-2 human pancreatic carcinoma cells were treated in vitro for 24 h with IMC-C225 (5 microg/mL), then exposed to epidermal growth factor (EGF) (10 mM) for 5 min. Immunoblots were screened for EGFR expression and the ability of IMC-C225 to block EGF-induced tyrosine phosphorylation of EGFR.
Apoptosis induction is a promising approach for cancer gene therapy. Bax is a death-promoting member of the Bcl2 family of genes that are intimately involved in apoptosis. Overexpression of BAX protein can accelerate cell death by homodimers that promote apoptosis in a variety of cancer cell lines.
View Article and Find Full Text PDF