Abstract:
BACKGROUND:Antibody Directed Enzyme Prodrug Therapy (ADEPT) can be used to generate cytotoxic agents at the tumor site. To date non-human enzymes have mainly been utilized in ADEPT. However, these non-human enzymes are immunogenic limiting the number of times that ADEPT can be administered. To overcome the problem of immunogenicity, a fully human enzyme, capable of converting a non-toxic prodrug to cytotoxic drug was developed and joined to a human tumor specific scFv yielding a fully human targeting agent. METHODS:A double mutant of human purine nucleoside phosphorylase (hDM) was developed which unlike the human enzyme can cleave adenosine-based prodrugs. For tumor-specific targeting, hDM was fused to the human anti-HER2/neu single chain Fv (scFv), C6 MH3B1. Enzymatic activity of hDM with its natural substrates and prodrugs was determined using spectrophotomeric approaches. A cell proliferation assay was used to assess the cytotoxicity generated following conversion of prodrug to drug as a result of enzymatic activity of hDM. Affinity of the targeting scFv, C6 MH3B1 fused to hDM to Her2/neu was confirmed using affinity chromatography, surface plasmon resonance, and flow-cytometry. RESULTS:In vitro hDM-C6 MH3B1 binds specifically to HER2/neu expressing tumor cells and localizes hDM to tumor cells, where the enzymatic activity of hDM-C6 MH3B1, but not the wild type enzyme, results in phosphorolysis of the prodrug, 2-fluoro-2'-deoxyadenosine to the cytotoxic drug 2-fluoroadenine (F-Ade) causing inhibition of tumor cell proliferation. Significantly, the toxic small drug diffuses through the cell membrane of HER2/neu expressing cells as well as cells that lack the expression of HER2/neu, causing a bystander effect. F-Ade is toxic to cells irrespective of their growth rate; therefore, both the slowly dividing tumor cells and the non-dividing neighboring stromal cells that support tumor growth should be killed. Analysis of potential novel MHCII binding peptides resulting from fusion of hDM to C6 MH3B1 and the two mutations in hDM, and of the structure of hDM compared to the wild-type enzyme suggests that hDM-C6 MH3B1 should exhibit minimal immunogenicity in humans. CONCLUSION:hDM-C6 MH3B1 constitutes a novel human based protein that addresses some of the limitations of ADEPT that currently preclude its successful use in the clinic.
journal_name
J Exp Clin Cancer Resjournal_title
Journal of experimental & clinical cancer research : CRauthors
Afshar S,Olafsen T,Wu AM,Morrison SLdoi
10.1186/1756-9966-28-147subject
Has Abstractpub_date
2009-12-03 00:00:00pages
147eissn
0392-9078issn
1756-9966pii
1756-9966-28-147journal_volume
28pub_type
杂志文章abstract:BACKGROUND:Investigation of the expression of an intestinal stem cell marker in esophageal adenocarcinomas (EAC) with and without Barrett's Esophagus (BE), with respect to a cancer stem cell (CSC) hypothesis. MATERIALS AND METHODS:Expression of a putative intestinal stem cell marker LgR5 was analyzed in esophageal can...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/1756-9966-30-23
更新日期:2011-02-23 00:00:00
abstract:BACKGROUND:Acute myeloid leukemia (AML) is initiated and maintained by a unique, small subset of leukemia stem cells (LSCs). LSCs are characterized by unrestricted self-renewal and contribute to the malignancy of leukemia. Aberrant protein fucosylation is associated with AML progression. However, it is still less under...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-019-1179-y
更新日期:2019-05-16 00:00:00
abstract:BACKGROUND:The deubiquitinase USP7 has been identified as an oncogene with key roles in tumorigenesis and therapeutic resistance for a series of cancer types. Recently small molecular inhibitors have been developed to target USP7. However, the anticancer mechanism of USP7 inhibitors is still elusive. METHODS:Cell viab...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-019-1457-8
更新日期:2019-11-15 00:00:00
abstract::Preclinical research and ongoing clinical trials are validating epidermal growth factor receptor (EGFR) as a suitable molecular target in cancer therapy. Here we report the case of a 39-year-old non-smoking man with heavily pretreated stage IV bronchioloalveolar NSCLC who was treated with gefitinib ('Iressa', ZD1839) ...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:2003-09-01 00:00:00
abstract:BACKGROUND:This study was conducted to investigate the expression of CXCR4 in portal vein tumor thrombus (PVTT) tissue and its possible role in the invasiveness of tumor thrombus cells. METHODS:We detected differential expression of CXCR4 between PVTT and hepatocellular carcinoma (HCC) by an immunohistochemical assay....
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/1756-9966-29-156
更新日期:2010-11-27 00:00:00
abstract:BACKGROUND:Bone metastasis is a leading cause of morbidity and mortality in advanced prostate cancer (PCa). Downexpression of miR-133a-3p has been found to contribute to the progression, recurrence and distant metastasis in PCa. However, clinical significance of miR-133a-3p in bone metastasis of PCa, and the biological...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-018-0813-4
更新日期:2018-07-18 00:00:00
abstract::The aim of this study was to investigate serum levels of IL-2, IL-6 and IL-10 in the pretreatment period and to determine if high IL-2, IL-6, IL-10 levels correlate with the outcome in patients with Non-Hodgkin's Lymphoma (NHL) in the post treatment period. Forty-three patients with the diagnosis of aggressive NHL wer...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:2004-09-01 00:00:00
abstract::Over the past 20 years, fiberoptic endoscopy, followed by video-endoscopy, has taken on an increasingly important role in the diagnostics and therapy for digestive tract diseases. Especially in the field of oncology, endoscopy is fundamental not only for the diagnosis and staging of diseases of the gastroenteric tract...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章,评审
doi:
更新日期:1999-03-01 00:00:00
abstract:BACKGROUND:Pancreatic cancer is a lethal disease in part because of its potential for aggressive invasion and metastasis. Lipoxin A4 (LXA4) is one of the metabolites that is derived from arachidonic acid and that is catalyzed by 15-lipoxygenase (15-LOX), and it has recently been reported to exhibit anti-cancer effects....
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-017-0655-5
更新日期:2017-12-11 00:00:00
abstract:BACKGROUND:Osteosarcoma (OS) is a high-grade bone sarcoma with early metastasis potential, and the clinical chemotherapy drugs that are currently used for its treatment have some limitations. Recently, several studies have reported the selective antitumor effect of oleandrin on various tumor cells. In this study, we ai...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-015-0232-8
更新日期:2015-10-06 00:00:00
abstract::Myelodysplastic syndromes (MDS) are a heterogenous group of hematological clonal malignancies. Patients belonging to the refractory anemia (RA) subtype are usually treated with recombinant human erythropoietin (EPO). Not all patients respond to EPO administration and they are strictly dependent on supportive therapy w...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:2004-03-01 00:00:00
abstract::The chemical modification of RNA is a newly discovered epigenetic regulation mechanism in cells and plays a crucial role in a variety of biological processes. N6-methyladenine (m6A) mRNA modification is the most abundant form of posttranscriptional RNA modification in eukaryotes. Through the development of m6A RNA seq...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章,评审
doi:10.1186/s13046-020-01706-8
更新日期:2020-09-17 00:00:00
abstract:BACKGROUND:Although significant progress has been made in the treatment of lymphomas, many lymphomas exhibit resistance to cell death, suggesting a defective Fas signaling, which remains poorly understood. We previously reported that cells expressing the K1 protein of human herpesvirus 8 (HHV-8) resist death through th...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/1756-9966-31-69
更新日期:2012-08-28 00:00:00
abstract:BACKGROUND:The sustained growth of tumors necessitates neovascularization. As one of the potent endogenous vascular inhibitors, endostatin has been widely used in antiangiogenesis therapy for tumor. Cisplatin is normally administered in chemotherapy for lung cancer but accompanied with serious side effects. In the curr...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/1756-9966-28-31
更新日期:2009-03-05 00:00:00
abstract::The efficacy of currently developed methods for gene transfer into mammalian cells depends primarily on the transfection technique, and also on the type of targeted cells. Considering the importance of gene transfer in the creation of gene therapies, our study was aimed at the assessment of transfection capacity of re...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:1999-12-01 00:00:00
abstract::The number of colorectal tumors per mouse induced by 1,2-dimethylhydrazine in transgenic (Tg) mice carrying human c-Ha-ras genes was significantly reduced by ingestion of apple pectin (AP) or a culture condensate of Bifidobacterium longum(MB) compared with a control diet and non-Tg mice. However, there were no differe...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:2001-03-01 00:00:00
abstract:BACKGROUND:Endometriosis is a gynecological disease defined by the histological presence of endometrial glands and stroma outside the uterine cavity. Women with endometriosis have an increased risk of different types of malignancies, especially ovarian cancer and non-Hodgkin's lymphoma. Though there are several theorie...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/1756-9966-28-49
更新日期:2009-04-09 00:00:00
abstract:BACKGROUND:Melanoma is a malignant tumor with high misdiagnosis rate and poor prognosis. The bio-targeted therapy is a prevailing method in the treatment of melanoma; however, the accompanying drug resistance is inevitable. SH2 superbinder, a triple-mutant of the Src Homology 2 (SH2) domain, shows potent antitumor abil...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-018-0812-5
更新日期:2018-07-05 00:00:00
abstract:BACKGROUND:Colon cancer is the second leading cancer worldwide. Recurrent disease and chemotherapeutic drug resistance are very common in the advanced stage of colon cancer. ATP-citrate lyase (ACLY), the first-step rate-controlling enzyme in lipid synthesis, is elevated in colon cancer. However, it remains unclear abou...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-019-1391-9
更新日期:2019-09-12 00:00:00
abstract::The aim of this work is the in vitro study of the late effects of single proton irradiation on HTB63 human melanoma cell growth, cell cycle and cell death. The experimental conditions were focused on analyzing the effects of irradiation on the periphery of tumour that can be, in clinical practice, close to critical or...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:2001-03-01 00:00:00
abstract::Distant metastases (DM) is the point of concern and seems to be on the rise with the improved control of the laryngeal cancer in the primary site and neck regions. Prognostic factors must be evaluated to improve the detection of DM at early stage of the disease. Therefore, we have analyzed our cases of laryngeal squam...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:1999-09-01 00:00:00
abstract::The rational making the G protein-coupled receptors (GPCR) the centerpiece of targeted therapies is fueled by the awareness that GPCR-initiated signaling acts as pivotal driver of the early stages of progression in a broad landscape of human malignancies. The endothelin-1 (ET-1) receptors (ET-1R), known as ETA recepto...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章,评审
doi:10.1186/s13046-021-01827-8
更新日期:2021-01-09 00:00:00
abstract:BACKGROUND:Chronic myelogenous leukemia (CML) is a myeloproliferative disorder caused by expression of the chimeric BCR-ABL tyrosine kinase oncogene, resulting from the t(9;22) chromosomal translocation. Imatinib (gleevec, STI-571) is a selective inhibitor of BCR-ABL activity highly effective in the treatment of CML. H...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-018-0843-y
更新日期:2018-07-25 00:00:00
abstract::The present study assesses the adaptation of a group of female patients with either manifest or suspected breast cancer who have undergone Magnetic Resonance Imaging (MRI) after receiving psychological support. Several studies in literature have reported the effectiveness of such support in reducing anti-oxidant and d...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:2006-12-01 00:00:00
abstract:BACKGROUND:The importance of individual microRNAs (miRNAs) in tumor has been established in different cancers. However, their association with tumor chemoresistance has not been fully understood. Previously, we found two novel MDR-associated microRNAs (miRNAs). In this report, we investigated the combined effects of mi...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-016-0300-8
更新日期:2016-02-03 00:00:00
abstract:BACKGROUND:Our previous studies have confirmed that cobalt chloride (CoCl2) can induce the formation of polyploid giant cancer cells (PGCCs), which is the key to the heterogeneity of solid tumors. PGCC formation is closely related to the abnormal expression of cell cycle-related proteins and cell fusion. In this study,...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-020-01588-w
更新日期:2020-05-11 00:00:00
abstract::The effect of malignant tumor growth on host's megakaryocytopoiesis and platelet production was studied in mice bearing transplantable Dalton's lymphoma. Tumor growth was paralleled by thrombocytosis, neutrophilia, and anemia. Platelet 51Cr half-life was normal but incorporation of 75Selenomethionine into circulating ...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:2000-12-01 00:00:00
abstract:BACKGROUND:To determine the expression of bone morphogenetic protein-2 (BMP-2) and its receptors BMPRIA, BMPRIB, and BMPRII in epithelial ovarian cancer (EOC) and to analyze their influence on the prognosis of ovarian cancer patients. METHODS:Semi-quantitative RT-PCR and western blot were applied to detect the express...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/1756-9966-29-85
更新日期:2010-06-30 00:00:00
abstract::Few cases of malignant glucagonomas have been described in the literature. In this paper we present a case of a 77-year-old woman with necrolytic migratory erythema and high plasma glucagon and chromogranin A levels caused by a neuroendocrine tumour. An abdominal CT scan suggested a pancreatic lesion and two liver met...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:2006-03-01 00:00:00
abstract:BACKGROUND:Increased serum level of parathyroid hormone (PTH) was found in metastatic prostate cancers. Calcimimetic R-568 was reported to reduce PTH expression, to suppress cell proliferation and to induce apoptosis in parathyroid cells. In this study, we investigated the effect of R-568 on cellular survival of prosta...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/1756-9966-28-100
更新日期:2009-07-14 00:00:00