Abstract:
:Traditional chemotherapeutic drugs are often restricted by severe side effects and lack of tumor specificity. Peptide prodrugs cleavable by peptidases present in the tumor environment have been explored to improve the therapeutic index of cytotoxic drugs. One such prodrug of doxorubicin (Dox), CPI-0004Na [N-succinyl-beta-alanyl-L-leucyl-L-alanyl-L-leucyl-Dox (sALAL-Dox)] has been shown to have an improved antitumor efficacy profile with reduced toxicity compared with Dox in tumor xenograft models (V. Dubois et al., Cancer Res., 62: 2327-2331, 2002). In this study, we demonstrate that CD10, a cell surface metalloprotease expressed on a variety of tumor cell types, is capable of cleaving CPI-0004Na and related peptide prodrugs such as N-succinyl-beta-alanyl-L-isoleucyl-L-alanyl-L-leucyl-Dox (sAIAL-Dox). This proteolytic cleavage generates leucyl-Dox, which is capable of entering cells and generating intracellular Dox. In a [(3)H]thymidine proliferation assay, analogues of CPI-0004Na showed a 100-300-fold increase in potency on CD10(+) cells compared with CD10(-) cells. Cytotoxicity of CPI-0004Na was inhibited by phosphoramidon, a known inhibitor of CD10 enzymatic activity. Furthermore, Chinese hamster ovary CHO-S cells, which are resistant to CPI-0004Na, could be sensitized to the cytotoxic effect of the prodrug by transfection of a CD10 cDNA. Tumor xenograft studies using LNCaP prostate tumor cells support the important role of CD10 in the antitumor efficacy of these prodrugs against tumors expressing CD10. CPI-0004Na and sAIAL-Dox achieved statistically significant 70% tumor growth inhibition at day 22. CD10 is expressed on many types of human tumors including B-cell lymphoma, leukemia, and prostate, breast, colorectal, and lung carcinomas; therefore, CD10-cleavable prodrugs may be effective in a range of different tumor types.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Pan C,Cardarelli PM,Nieder MH,Pickford LB,Gangwar S,King DJ,Yarranton GT,Buckman D,Roscoe W,Zhou F,Salles A,Chen TH,Horgan K,Wang YH,Nguyen T,Bebbington CRsubject
Has Abstractpub_date
2003-09-01 00:00:00pages
5526-31issue
17eissn
0008-5472issn
1538-7445journal_volume
63pub_type
杂志文章相关文献
CANCER RESEARCH文献大全abstract::We have used genome-wide allelotyping with 348 polymorphic autosomal markers spaced, on average, 10 cM apart to quantitate the extent of intrachromosomal instability in 59 human sporadic colorectal carcinomas. We have compared instability measured by this method with that measured by inter-(simple sequence repeat) PCR...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2001-11-15 00:00:00
abstract::ARID1A, encoding a subunit of the SWI/SNF complex, is the most frequently mutated epigenetic regulator in human cancers and is mutated in more than 50% of ovarian clear cell carcinomas (OCCC), a disease that currently has no effective therapy. Inhibition of histone deacetylase 6 (HDAC6) suppresses the growth of ARID1A...
journal_title:Cancer research
pub_type: 评论,杂志文章
doi:10.1158/0008-5472.CAN-19-1302
更新日期:2019-11-01 00:00:00
abstract::Immune effector cells integrate signals that define the nature and magnitude of the subsequent response. Experimental measures for immune cell-mediated lysis of tumors or virally infected targets rely on average responses of permeability or apoptotic changes within a population of targets. Here, we examined individual...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-11-3396
更新日期:2012-06-15 00:00:00
abstract::We have designed a novel peptide, DP1, which is able to mediate significant induction of apoptosis in solid tumors by local injection. This peptide, comprised of a protein transduction domain (PTD), PTD-5, fused to an antimicrobial peptide, (KLAKLAK)2, was able to trigger rapid apoptosis in a variety of cell lines in ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2001-11-01 00:00:00
abstract::We studied the effects of interleukin-1 alpha (IL-1) and interleukin-6 (IL-6) on MCF-7 breast cancer cells to determine whether these cytokines act additively/synergistically to alter cell growth and metabolism. We found that IL-1 alone (1000 units/ml) inhibited cell growth to a greater degree (83.8%) than IL-6 alone ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1993-04-01 00:00:00
abstract::The Notch signaling pathway is required in both nonneoplastic neural stem cells and embryonal brain tumors, such as medulloblastoma, which are derived from such cells. We investigated the effects of Notch pathway inhibition on medulloblastoma growth using pharmacologic inhibitors of gamma-secretase. Notch blockade sup...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-06-0858
更新日期:2006-08-01 00:00:00
abstract::Increased neovascularization and vascular hyperpermeability are integral processes in tumors, and various therapeutic strategies seek to reverse the angiogenic phenotype. Long-circulating liposomes extravasate in tumors such as the rat 9L gliosarcoma and accumulate in perivascular areas. Under such conditions, liposom...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2002-05-01 00:00:00
abstract::Monocytes and dendritic cells are key players in the immune response. Because dendritic cells drive the tumor host defense, it is important that monocytes and dendritic cells survive cytotoxic tumor therapy. Although most of the anticancer drugs target DNA, the DNA repair capacity of monocytes and dendritic cells has ...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-06-3712
更新日期:2007-01-01 00:00:00
abstract::1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] inhibited the secretion of gamma-interferon from human T-lymphocytes activated by the calcium ionophore, A23187, or phytohemagglutinin with or without 12-O-tetradecanoylphorbol-13-acetate. The agent also inhibited cell proliferation and interleukin 2 secretion by these cells. Th...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1986-11-01 00:00:00
abstract::Little is known about the genetic and molecular events leading to the early stages of human astrocytoma formation. To examine this issue, we analyzed the significance of sequential accumulation of two somatic point mutations (R267W and E258D) in the TP53 gene during the initiation of astrocytoma in a patient born with...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2002-05-15 00:00:00
abstract::The Morris hepatocellular carcinoma 7777 is productive of extraordinarily high levels of the oncofetal protein, alpha-fetoprotein. Its chromosome composition was examined in detail since it represents the only near-diploid tumor of such productivity and has been reported to demonstrate a single unusual chromosomal alt...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1977-08-01 00:00:00
abstract::Microarray gene expression profiling is a powerful tool for generating molecular cancer classifications. However, elucidating biological insights from these large data sets has been challenging. Previously, we identified a gene expression-based classification of primary uveal melanomas that accurately predicts metasta...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-05-4196
更新日期:2006-05-01 00:00:00
abstract::c-myc expression, amplification, and rearrangement were studied in neoplastic hepatic nodules of rats after diethylnitrosamine treatment, in hepatocellular carcinomas induced by N-methyl-N-nitrosourea, and in tumorigenic liver cell lines derived from rat hepatocytes transformed by diethylnitrosamine in vivo. Steady-st...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1989-12-01 00:00:00
abstract::A megakaryoblastic cell line, termed T-33, was established from the peripheral blood of a patient with Philadelphia chromosome-positive chronic myelogenous leukemia in megakaryoblastic crisis. T-33 cells have been maintained in RPMI 1640 medium containing 10% fetal calf serum in a single cell suspension with a doublin...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1988-11-01 00:00:00
abstract::Inhibition of PACE4, a proprotein convertase that is overexpressed in prostate cancer, has been shown to block cancer progression in an androgen-independent manner. However, the basis for its overexpression and its growth-inhibitory effects are mitigated and uncertain. Here, we report that PACE4 pre-mRNA undergoes DNA...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-17-1397
更新日期:2017-12-15 00:00:00
abstract::Estrogen receptor-related receptors (ERR) are orphan nuclear receptors, which are constitutively activated without estrogen binding. Recent evidence indicates that the ligand-independent ERRs may be involved in similar ER-mediated regulatory pathways and modulate estrogen responsiveness in certain target cells. We rec...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-06-3855
更新日期:2007-05-15 00:00:00
abstract::We previously showed that RhoA played an important role in the proliferation of murine We prostate cancer (TRAMP) cells (P. M. Ghosh et al., Oncogene, 18: 4120-4130, 1999). Untransfected TRAMP cells as well as those expressing constitutively active RhoA (Q63L) mutant protein (Q63L cells) were highly proliferative. In ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2002-05-01 00:00:00
abstract::Death receptor Fas-mediated apoptosis not only eliminates nonspecific and autoreactive B cells but also plays a major role in antitumor immunity. However, the possible mechanisms underlying impairment of Fas-mediated induction of apoptosis during lymphomagenesis remain unknown. In this study, we employed our developed...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-19-3993
更新日期:2020-10-15 00:00:00
abstract::Inactivation of p16INK4 tumor suppressor gene function is frequently observed in breast cancer. We examined p16INK4 expression in human mammary epithelial cell (HMEC) cultures established from four normal donors. Normal HMECs divide a limited number of times before proliferation ceases in a state referred to as select...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1998-08-15 00:00:00
abstract::In order to determine the potential role of sex steroid and 1,25-dihydroxyvitamin D3 in the spreading of colorectal cancer, previously hypothesized from epidemiological and experimental data, specific androgen (AR, n = 94), estrogen (ER, n = 60), progesterone (PGR, n = 50), and 1,25-dihydroxyvitamin D3 receptors (VDR,...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1991-02-15 00:00:00
abstract::The cellular effects of alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase (ODC), and N1,N8-bis(ethyl)spermidine (BES), an apparent regulator of the enzyme were compared in cultured L1210 cells. Unlike DFMO, BES has no direct inhibitory effect on ODC activity. Rather the polyamine analogue i...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1986-12-01 00:00:00
abstract::Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the nuclear receptor (NR) family of transcription factors with important regulatory roles in cellular growth, differentiation, and apoptosis. Using proteomic analysis, we showed expression of PPARgamma protein in a series of 260 newly diagnose...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-09-1962
更新日期:2010-06-15 00:00:00
abstract::As recently characterized, following s.c. implantation into syngeneic C57BL/6 mice, E0771 tumor invades locally into dermal layers and peritoneum, metastasizes to the lung, and induces a nonspecific immunosuppression in the host. Using this breast medullar adenocarcinoma model, a therapy consisting of a single moderat...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-05-3963
更新日期:2006-05-15 00:00:00
abstract::The increase of interleukin-4 (IL-4) level in tumor environment and the up-regulation of IL-4 receptor (IL-4R) on tumor cells have been long observed. However, their significance for tumor development has not been investigated. Here, we found that endogenous IL-4 promotes tumor growth because neutralizing IL-4 by 11B1...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-08-0449
更新日期:2008-11-01 00:00:00
abstract::Methyl methanesulfonate (MMS), a direct-acting alkylating agent, is a strong brain carcinogen but a poor hepatocarcinogen in rats. To elucidate the mechanism(s) leading to tissue-specific carcinogenesis in response to MMS, we compared the activation of the stress-activated protein kinases (SAPKs), the c-Jun NH2-termin...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2000-09-15 00:00:00
abstract::Recent investigations have documented that constitutively activated phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it strongly influences growth and survival. These findings lend compelling weight for the...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-08-4884
更新日期:2009-04-15 00:00:00
abstract::Aberrant promoter hypermethylation and associated gene silencing are epigenetic hallmarks of tumorigenesis. It has been suggested that aberrant DNA methylation can affect the sensitivity of cancers to antineoplastic agents by altering expression of genes critical to drug response. To study this issue, we used bisulfit...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-07-1502
更新日期:2007-12-01 00:00:00
abstract::MUC1 is a heterodimeric transmembrane glycoprotein that is overexpressed and aberrantly glycosylated in ductal adenocarcinomas. Differential phosphorylation of the MUC1 cytoplasmic tail (MUC1CT) has been associated with signaling events that influence the proliferation and metastasis of cancer cells. We identified a n...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-06-4647
更新日期:2007-06-01 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::It is becoming increasingly clear that tumor growth and progression is not entirely due to genetic aberrations but also reflective of tumor cell plasticity. It follows therefore that proteins contributing to tumor progression oscillate in their expression a contention yet to be shown. Because the urokinase-type plasmi...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-05-3208
更新日期:2006-08-15 00:00:00