Abstract:
:The prodrug of 9-beta-D-arabinosylguanine (ara-G), nelarabine, demonstrated efficacy against T-cell acute lymphoblastic leukemia, and its effectiveness correlated with the accumulation of the triphosphate form (ara-GTP). Although in vitro investigations using purified deoxycytidine kinase (dCK) or deoxyguanosine kinase (dGK) suggested that ara-G is a substrate for both enzymes, controversy exists in regard to the role of these enzymes in whole cells. In this work, we used a CEM mutant cell line containing low endogenous levels of dGK and deficient in dCK (dCK-) to assess the role of these kinases in ara-G phosphorylation. Using a retroviral vector system, we infected the dCK- mutant cell line to obtain cell lines with overexpression of dCK (dCK+) or dGK (dGK+). Only the dCK+ cell line phosphorylated 1-beta-D-arabinofuranosylcytosine (used as a substrate for dCK) in a cell-free system; phosphorylation of this compound by dGK+ was below the limit of detection. Again in in vitro assays, the dCK-and dCK+ cell lines phosphorylated dGuo to similar levels (0.91 +/- 0.15 and 0.93 +/- 0.19 pmol/mg/min, respectively), whereas dGK+ phosphorylated dGuo more efficiently (150 pmol at 60 min). When ara-G was used as a substrate in a cell-free system, the maximum accumulation of phosphorylated product was observed in dGK+ extracts at low ara-G levels (10 microM) and in dCK+ extracts at high concentrations of ara-G (100 microM). Thus, both dCK and dGK can phosphorylate ara-G, but at low ara-G concentrations, dGK seems to predominate, whereas at higher ara-G concentrations, dCK seems to be the preferred enzyme. In whole-cell systems after a 3-h incubation with 10 microM ara-G, both dCK+ and dGK+ cells accumulated ara-GTP; however, the levels were significantly (P = 0.0008) higher in dGK+ cells. In contrast, at 100 microM ara-G, intracellular ara-GTP accumulated to similar levels (P = 0.5529) in these cell types; 25 +/- 3.7 microM in dCK+, and 27.8 +/- 2.7 microM in the dGK+ cells. These results from whole-cell experiments are consistent with those from the cell-free system and strongly suggest that ara-G is phosphorylated by both kinases, and at low substrate concentrations, dGK is preferred enzyme. Evaluation of the expression of each of these kinases in primary leukemia cells may reveal a biochemical basis for the pharmacological differences in the accumulation of ara-GTP.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Rodriguez CO Jr,Mitchell BS,Ayres M,Eriksson S,Gandhi Vsubject
Has Abstractpub_date
2002-06-01 00:00:00pages
3100-5issue
11eissn
0008-5472issn
1538-7445journal_volume
62pub_type
杂志文章相关文献
CANCER RESEARCH文献大全abstract::The mechanism of latent membrane protein LMP1 of EBV in inducing cell transformation and tumorigenesis was investigated in Rat-1 fibroblasts. A plasmid encoding a site-specific mutant of LMP1 defective in binding to tumor necrosis factor receptor-associated death domain protein was constructed. This LMP1(TRADD) gene i...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2000-04-01 00:00:00
abstract::Induction of an apoptotic cell death was studied in a mouse T-cell hybridoma. Apoptosis was induced in these cells following exposure to dexamethasone, X-radiation, 43 degrees C heat shock, A254 light, and hydrogen peroxide. In 5-Gy-exposed cells, a radiation-induced G2 phase cell cycle progression block was maximum b...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1992-02-15 00:00:00
abstract::Previous studies have shown that PC12 cells undergo apoptosis (programmed cell death) when deprived of serum. In the present study, we examined the relationship of this death process to the cell cycle. PC12 cell populations synchronized at different, specific phases of the cell cycle exhibit similar kinetics of cell d...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1995-03-15 00:00:00
abstract::The mechanisms underlying the progression of prostate cancer to a state of resistance to hormone ablation remain poorly understood. Here, we have investigated the relationship between androgen receptor (AR) and Her-2/neu in prostate cancer cells. Overexpression of Her-2/neu (c-ErbB2) activates the AR pathway and confe...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-05-3928
更新日期:2006-06-01 00:00:00
abstract::We have established two new epithelial cell lines (NRP-152, NRP-154), with markedly different properties, from the dorsal-lateral prostate of Lobund/Wistar rats treated with N-methyl-N-nitrosourea and testosterone propionate. NRP-152 cells do not form tumors in athymic mice and retain many of the properties of normal ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1994-07-01 00:00:00
abstract::A deletion in an Alu repetitive sequence in the fifth intron of the c-sis gene of meningioma patients was previously described (M. Smidt et al., J. Clin. Invest., 86:1151-1157, 1990). The authors analyzed the structure of this intron in DNA from peripheral blood leukocytes and tumor samples of 86 patients with sporadi...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1991-08-15 00:00:00
abstract::The cytotoxicity of a diphtheria toxin-human epidermal growth factor fusion protein (DAB(389)EGF) was tested against 14 human glioma cell lines. After cells were cultured for 48 h with various concentrations of DAB(389)EGF, the percentage reduction in thymidine incorporation was determined. For 13 of 14 cell lines, po...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2003-04-15 00:00:00
abstract::Protein kinase Ciota (PKCiota) is an oncogene required for maintenance of the transformed phenotype of non-small cell lung cancer cells. However, the role of PKCiota in lung tumor development has not been investigated. To address this question, we established a mouse model in which oncogenic Kras(G12D) is activated by...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-09-2066
更新日期:2009-10-01 00:00:00
abstract::Human p29 is a newly identified nuclear protein whose function is largely undetermined. We found that p29 associated with chromatin, interacted with MCM3, and localized with proliferating cell nuclear antigen foci in the S phase. Silencing of p29 using small interfering RNA duplexes reduced DNA synthesis and increased...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-05-3229
更新日期:2006-09-01 00:00:00
abstract::The cytotoxic activity against human tumor cells of toxic conjugates of Pseudomonas exotoxin with anti-transferrin receptor antibody or epidermal growth factor was potentiated up to 10 to 20-fold by the calcium antagonists verapamil, D-600, and diltiazem and by the lysosomotropic agent beta-glycylphenyl-naphthylamide....
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1985-03-01 00:00:00
abstract::SOX9 [sex-determining region Y (SRY)-box 9 protein], a high mobility group box transcription factor, plays critical roles during embryogenesis and its activity is required for development, differentiation, and lineage commitment in various tissues including the intestinal epithelium. Here, we present functional and cl...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-11-3660
更新日期:2012-03-01 00:00:00
abstract::Potent luteinizing hormone-releasing hormone analogues are known to cause regression of hormone-dependent mammary tumors. We have observed that high and long-lasting serum levels of a potent luteinizing hormone-releasing hormone analogue [desglycyl10-(D-leucyl6) luteinizing hormone-releasing hormone ethylamide, leupro...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1983-04-01 00:00:00
abstract::Myeloma vaccines, based on dendritic cells pulsed with idiotype or tumor lysate, have been met with limited success, probably in part due to insufficient cross-priming of myeloma antigens. A powerful method to introduce myeloma-associated antigens into the cytosol of dendritic cells is protein transduction, a process ...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-05-1383
更新日期:2005-11-01 00:00:00
abstract::The carcinogenic effectiveness of a number of nitrosoalkylamides related to nitrosoethylurea and nitroso-n-propylurea has been compared by topical application to Swiss mice and by intragastric administration to F344 rats. Nitrosohydroxyethylurea and the related cyclic nitrosamide, nitrosooxazolidone, were as potent as...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1983-01-01 00:00:00
abstract::Radiation resistance poses a major clinical challenge in cancer treatment, but little is known about how microRNA (miR) may regulate this phenomenon. In this study, we used next-generation sequencing to perform an unbiased comparison of miR expression in PC3 prostate cancer cells rendered resistant to fractionated rad...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-13-1657
更新日期:2013-12-01 00:00:00
abstract::PR-104, currently in phase II clinical trials, is a phosphate ester pre-prodrug which is converted in vivo to its cognate alcohol, PR-104A, a prodrug designed to exploit tumor hypoxia. Bioactivation occurs via one-electron reduction to DNA crosslinking metabolites in the absence of oxygen. However, certain tumor cell ...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-09-3237
更新日期:2010-02-15 00:00:00
abstract::Although radiotherapy (RT) decreases the incidence of locoregional recurrence in breast cancer, patients with triple-negative breast cancer (TNBC) have increased risk of local recurrence following breast-conserving therapy. The relationship between RT and local recurrence is unknown. Here, we tested the hypothesis tha...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-17-3623
更新日期:2018-08-01 00:00:00
abstract::Radiation leukemia virus-induced leukemia of a male C57BL/6 mouse, B6RV2, is immunogenic to female BALB/c X C57BL/6 F1 mice. In these mice, B6RV2 tumors regressed after initial growth, and after tumor regression the mice were resistant to repeated inocula of up to 10(8) B6RV2 cells. Serum from these mice reacted with ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1984-11-01 00:00:00
abstract::Emerging technologies allow broad profiling of the cancer genome for differential DNA methylation relative to benign cells. Herein, bisulfite-modified DNA from lymph nodes with either reactive hyperplasia or follicular lymphoma (FL) were analyzed using a commercial C/UpG genotyping assay. Two hundred fifty-nine differ...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-08-2984
更新日期:2009-02-01 00:00:00
abstract::Two human pancreatic cell lines, MIA PaCa 2 and Capan 2, were treated by photodynamic therapy in vitro with Photophrin (0.01-25 micrograms/ml; 24 h) and then light (1-50 J/cm2; lambda = 630 nm). The following model was fit to 6 datasets with weighted nonlinear regression: [sequence: see text] The symbols are: E, cell ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1995-07-15 00:00:00
abstract::The purpose of this study was to evaluate the efficacy of treatment with recombinant interleukin-2 (rIL-2) and lymphokine-activated killer cells in patients with advanced bladder cancer and to study the induced changes in the distribution of leukocyte subsets in blood and tumor. Nine patients with metastatic transitio...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1992-02-01 00:00:00
abstract::Five of six rat sarcomas, induced by the Schmidt-Ruppin (SR) strain of avian tumor virus, expressed a Mr 60,000 tumor cell surface antigen (TSA), immunoprecipitable from non-ionic detergent extracts. Expression of the antigen was exclusive to rat cells transformed by the SR virus strain. Moreover, expression of TSA ap...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1986-11-01 00:00:00
abstract::The insulin-like growth factor-1 receptor (IGF-1R) plays a pivotal role in transformation, growth, and survival of malignant cells, and has emerged as a general and promising target for cancer treatment. However, no fully selective IGF-1R inhibitors have thus far been found. This is explained by the fact that IGF-1R i...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.can-03-2522
更新日期:2004-01-01 00:00:00
abstract::Mitochondria are the powerhouses of cells. Mitochondrial C-Raf is a potential cancer therapeutic target, as it regulates mitochondrial function and is localized to the mitochondria by its N-terminal domain. However, Raf inhibitor monotherapy can induce S338 phosphorylation of C-Raf (pC-Raf(S338)) and impede therapy. T...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-14-3264
更新日期:2015-09-01 00:00:00
abstract::T cells expressing human leukemia virus (HTLV) type 1, the etiological agent of adult T-cell leukemia, are remarkably resistant to conventional chemotherapy, and the need for drugs that effectively kill these cells is apparent. Here we show that roscovitine, an inhibitor of cyclin-dependent kinases (CDKs), induces the...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2003-12-01 00:00:00
abstract::3,4-Dihydro-2,2-dimethyl-2H-naptho[1,2,-b]pyran-5,6-dione (beta-lapachone) is a novel DNA repair inhibitor. It was tested for synergistic X-ray-induced lethality in combination with several halogenated pyrimidine radiosensitizers. Logarithmic-phase growing human epidermoid laryngeal carcinoma (HEp-2) cells were allowe...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1987-10-15 00:00:00
abstract::A large number of studies have been carried out to identify the Friend leukemia virus (FV) target cell(s). In FV-infected mice, the kinetics of "primitive" erythroid burst-forming units (P-BFU-E) is perturbed, and their proliferative rate is enhanced. These results indirectly suggest, but do not prove, that cycling P-...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1983-02-01 00:00:00
abstract::Experiments were performed to assess the role of liver cell necrosis in the induction of early steps in liver carcinogenesis with diethylnitrosamine, as measured by the appearance of foci of resistant hepatocytes that stain for gamma-glutamyl transpeptidase and that are presumptive preneoplastic lesions in the rat. Wi...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1981-06-01 00:00:00
abstract::Invasive lobular and ductal breast tumors have distinct histologies and clinical presentation. Other than altered expression of E-cadherin, little is known about the underlying biology that distinguishes the tumor subtypes. We used cDNA microarrays to identify genes differentially expressed between lobular and ductal ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2003-11-01 00:00:00
abstract::The cultivated mushroom of commerce in the Western hemisphere, Agaricus bisporus, was given p.o. to randomly bred Swiss mice for 3 days and was followed by semisynthetic diet for 4 days each week for life. The mice were 6 weeks old at the beginning of the experiment. As a result of treatment, tumors were induced in th...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1986-08-01 00:00:00