Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two genes encode the CD16 low affinity IgG FcR. CD16-I (Fc gamma RIII-1) is expressed on PMN as a phosphatidylinositol-glycan anchored glycoprotein. CD16-II (Fc gamma RIII-2) is expressed on NK cells and macrophages as a transmembrane glycoprotein associated with CD3 zeta or Fc epsilon RI-gamma. NK cells spontaneously release soluble CD16-II from the cell surface and this is enhanced by activation with phorbol ester. In this study, we demonstrate that a metalloprotease is involved in the spontaneous and PMA-induced release of CD16-II from NK cells. 1,10-phenanthroline, an inhibitor of Zn(2+)-dependent metalloproteases, efficiently inhibits CD16-II release. 1,7-phenanthroline, an inactive analogue that doesn't chelate Zn2+ or other divalent metal cations, and inhibitors of serine proteases do not affect spontaneous or PMA-induced release of CD16-II. Murine P815 mastocytoma cells transfected with human CD16-II cDNA shed membrane CD16, and 1,10-phenanthroline inhibits this process. P815 transfectants expressing CD16-II molecules with truncated cytoplasmic domains also release soluble receptors, indicating that the cytoplasmic segment of CD16-II is not required for interaction with the protease or the cytoskeleton. By contrast, 1,10-phenanthroline does not inhibit PMA-induced release of CD16-I glycoprotein from PMN, indicating a different mechanism of release for this phosphatidylinositol-glycan anchored molecule. Prior studies have demonstrated that NK cells are activated via the inositol phosphate pathway after engagement of CD16-II by immune complexes or Ig-coated tumor cell targets. A membrane metalloprotease with substrate specificity for CD16-II that is activated by PKC stimulation may provide a mechanism for releasing the immune complex or target from the effector cells and halting signal transduction.
 ...
PMID:Involvement of a metalloprotease in spontaneous and phorbol ester-induced release of natural killer cell-associated Fc gamma RIII (CD16-II). 183 41

Prostaglandin E2 (PGE2, 5 ng/ml to 5 micrograms/ml) induced a dose-dependent increase in cAMP accumulation, inositol phosphates (IPs) accumulation, and cytoplasmic free Ca2+ ([Ca2+]i) in a clonal osteoblast-like cell line, MOB 3-4. In contrast, prostaglandin F2 alpha (PGF2 alpha, 5 ng/ml to 5 micrograms/ml) stimulated increases in IPs accumulation and [Ca2+]i without stimulating an increase in cAMP accumulation. Both PGE2 (greater than 0.5 micrograms/ml) and PGF2 alpha (greater than or equal to 5 micrograms/ml) increased cytoplasmic pH (pHi) from approximately 7.15 to 7.35 in BCECF-loaded cells. A tumor promotor, phorbol 12-myristate 13-acetate (PMA, 0.1-100 nM) also increased pHi without effect on phosphoinositide hydrolysis. Both PGE2-(5 micrograms/ml) and PMA- (100 nM) induced cytoplasmic alkalinization was inhibited by removal of extracellular Na+, or by pretreatment of the cells with amiloride (0.5 mM), an inhibitor of Na+/H+ exchange, or H-7 (100 microM), a nonspecific inhibitor of protein kinase C. Thus, MOB 3-4 cells appeared to possess PGE2 receptors and PGF2 alpha receptors: the former are coupled to adenylate cyclase and phospholipase C, and the latter are predominantly coupled to phospholipase C. Also the cells appeared to possess an amiloride-sensitive Na+/H+ exchange activity, which increases pHi in response to PGE2 and PGF2 alpha, as well as to PMA. Long-term (48 hr) exposure of the cells to PGE2 at a high concentration (5 micrograms/ml), but not to PGF2 alpha and PMA, decreased DNA synthesis in the serum-deficient medium. Thus, cytoplasmic alkalinization appeared insufficient for cell replication. At least in MOB 3-4 cells, the inhibitory effect of PGE2 on DNA synthesis may be due to the cAMP messenger system.
 ...
PMID:Effects of prostaglandin E2 and F2 alpha on cytoplasmic pH in a clonal osteoblast-like cell line, MOB 3-4. 184 35

The human aldolase A gene is transcribed from three distinct promoters, the two ubiquitous promoters PN and PH and the muscle specific promoter PM. In the present study, we investigate further aldolase A mRNA structure and expression. We demonstrate that the upstream N-type exon is, in fact, extremely heterogeneous. RNAse H mapping experiments permit quantification of relative abundance of N, M, and H type mRNAs and show that the level of transcripts containing the downstream H-type exon is at least 30 times higher than that of those containing N exon, in all tissues tested. Aldolase A level is up-regulated in proliferating cells. Here we show that both N and H type mRNAs, although barely detectable in normal liver, are highly expressed in human hepatomas biopsies. Furthermore, in human lymphocytes, N-type mRNA level is enhanced by serum treatment, while in cultured Hep G2 cells, both N-type and H-type mRNA levels are increased by serum and by the tumor promoting agent PMA. Using CAT constructs in transfection experiments, we demonstrate that the H exon plus its upstream region can function autonomously: the 420 base pairs upstream of the H exon are sufficient to confer to promoter PH an efficiency comparable that of the complete SV40 early promoter and enhancer in two cell lines.
 ...
PMID:Regulation of the multiple promoters of the human aldolase A gene: response of its two ubiquitous promoters to agents promoting cell proliferation. 185 Jan 23

177Lutetium (177Lu) is a member of the family of elements known as lanthanides or rare earths. Monoclonal antibody (MAb) CC49, a murine IgG1, which is reactive with the tumor-associated antigen, TAG-72, has been shown previously to react with a wide range of human carcinomas; CC49 reacts to a different epitope on the TAG-72 molecule than MAb B72.3 and has a higher binding affinity. We report here the first use of a 177Lu-labeled immunoconjugate, 177Lu-CC49, in an experimental therapy model for human carcinoma. 177Lu-CC49 was shown to delay the growth of established LS-174T human colon carcinomas in athymic mice at a single dose of 50 microCi. Overt toxicity was observed with the administration of approximately 500 microCi of 177Lu-CC49 in which 5 of 9 mice died of apparent marrow toxicity. A single administration of 200 or 350 microCi of 177Lu-CC49, however, was shown to eliminate established tumors through the 77-day observation period after MAb administration. Dose fractionation experiments revealed that at least 750 microCi of 177Lu-CC49 (250 microCi/week for 3 consecutive weeks) was well tolerated in that 9 of 10 mice survived. Moreover, this dose schedule was able to eliminate the growth of relatively large (300 mm3) human colon tumor xenografts in 90% of the animals treated. Single-dose and dose fractionation studies were also carried out with an isotype-matched control MAb, 177Lu-MOPC-21. In all dose schedules, a large differential was seen between the therapeutic effects of the 177Lu-CC49 versus that of the 177Lu-control MAb. The merits and limitations of the use of 177Lu-labeled immunoconjugates (in particular, 177Lu-CC49) are discussed in terms of potential novel therapeutics for human carcinoma.
 ...
PMID:Monoclonal antibody-based therapy of a human tumor xenograft with a 177lutetium-labeled immunoconjugate. 185 65

The administration of [131I]B72.3 MAb for both diagnostic and therapeutic purposes is followed by the development of human anti-mouse antibodies (HAMA) in approx. 70% of patients receiving i.v. doses of MAb above 1 mg. The presence of HAMA in circulation interferes in the detection of the tumor-associated glycoprotein TAG-72 using the CA 72-4 RIA. We have reported elsewhere (Ferroni et al., 1990) that heat treatment at 90 degrees C, pH 6.5, for 15 min is capable of precipitating and/or inactivating HAMA without causing any significant loss in antigen recovery. Furthermore, the removal of the interfering activity leads to a more correct evaluation of TAG-72 serum levels in HAMA-positive serum samples and to a continued use of TAG-72 in the follow-up of patients undergoing MAb-based clinical protocols.
 ...
PMID:Potential artifact for the increase of tumor associated antigens in serum samples from patients injected with monoclonal antibodies. 186 26

Monoclonal antibodies against a tumor-associated antigen (TAG-72) with mucin-like properties have been generated. MAb B72.3 was used to identify and help characterize this antigen. B72.3 has been successfully used for the localization of tumor metastases in situ after i.v. administration. MAb B72.3 has also been used in conjunction with CC49, another anti-TAG-72 MAb, to measure TAG-72 levels in sera and effusions. TAG-72 can be found in the fluids of patients with adenocarcinomas from many different sites. This CA 72-4 double determinant radioimmunoassay in conjunction with assays for carcinoembryonic antigen can identify patients with malignancies with greater sensitivity than either assay alone.
 ...
PMID:In vivo and in vitro clinical applications of monoclonal antibodies against TAG-72. 186 28

A novel tumor marker, tumor-associated glycoprotein-72 (TAG-72), has been identified using monoclonal antibody (MAb) B72.3. Using immunohistochemical techniques, TAG-72 has been found in carcinomas of various origin including colon, stomach, breast, lung, prostate, and ovary, as well as in body fluids. The presence of TAG-72 in serum samples from 260 patients with colorectal disease (malignant or benign) has been evaluated using the CA72-4 assay. Approximately 40% of patients with colorectal cancer exhibit elevated levels of this marker; moreover, the presence of positive levels of TAG-72 significantly correlates with advanced stages of disease, suggesting that TAG-72 may be a good marker of advanced colorectal cancer. Only 2% of the patients diagnosed with colorectal disease had elevated TAG-72 serum levels indicating the high specificity of this marker. A comparative study with carcinoembryonic antigen (CEA) serum levels showed a complementarity of the two tumor markers; in fact, 49.6% of CEA negative cases scored positive for TAG-72. A longitudinal evaluation of TAG-72 serum levels in 31 patients with malignant disease was performed. The results indicate that patients with increasing TAG-72 serum levels postoperatively may be indicative of recurrent disease. In 60% of patients in which significant changes of CEA levels could not be detected, TAG-72 showed rising positive levels prior to clinical evidence of recurrent disease. These results suggest that the simultaneous use of TAG-72 and CEA serum markers may be useful in the diagnosis of recurrent disease and therefore play an important role in the clinical management of cancer patients.
 ...
PMID:Clinical evaluation of serum tumor-associated glycoprotein-72 as a novel tumor marker for colorectal cancer patients. 189 26

Human Platelet Derived Growth Factors (PDGF) are potent mitogens for mesenchymal cells and encoded by two related genes, the A- (or 1-) and B- (or 2-) chain. The latter is known as the human homolog (c-sis) of the v-sis oncogene. We investigated the expression and cytokine-mediated regulation of PDGF A- and B-chain mRNA in endoderm-derived cells, i.e. cultured human pancreatic adenocarcinoma cells. Northern blot analysis revealed that out of 14 cells lines 11 were positive for the A-chain and 10 for the B-chain. Tumor Necrosis Factor (TNF) -alpha and -beta, but not Interferon (IFN) -gamma, drastically upregulate the mRNA levels for PDGF B-chain and for the A-chain in a dose-dependent manner in nearly every pancreatic tumor cell line investigated (n = 6). With respect to the signal pathway stimulated by TNF, no evidence emerged for an activation of protein kinase A. The inhibition of protein kinase C by staurosporine (in the absence or presence of TNF) as well as its stimulation by PMA resulted in an increased mRNA level for the B-chain, indicating a functional role of PKC in this system. Furthermore, time course experiments and Cycloheximide treatment showed that the A- and B-chain mRNA are regulated by different mechanisms in transformed epithelial cells. Irrespective of these differences, the sum of their biological functions may contribute to the phenomenon of desmoplasia in pancreatic tumors by epithelial/mesenchymal interactions.
 ...
PMID:Modulation of platelet-derived growth factor A- and B-chain/c-sis mRNA by tumor necrosis factor and other agents in adenocarcinoma cells. 190 54

In vitro treatment with either type I or type II interferon (IFN) can selectively enhance the expression of several tumor antigens, such as the carcinoembryonic antigen (CEA) and the tumor-associated glycoprotein-72 (TAG-72) in different human carcinoma cell lines and result in enhanced level of monoclonal antibody (MAb) binding to the cell surface. In vivo animal studies demonstrated that treatment of athymic mice with a type I interferon [i.e. interferon-alpha (A)] significantly increased the expression of a 90 kDa tumor antigen which improved the targeting of a MAb to the carcinoma xenograft. More recent studies reported that in vitro IFN treatment of human adenocarcinoma cells isolated from human malignant serous effusions selectively increased the expression of TAG-72 and CEA. One can envision that the ability of these cytokines to upregulate the level of expression of human tumor antigens presents an important experimental model in which to study the regulation of markers often correlated with epithelial cell differentiation. In addition, the increase of selective MAb-defined antigens may also be exploited in an adjuvant setting to localize higher amounts of MAbs to the tumor cell surface and, thereby, improve the effectiveness of a MAb for tumor diagnosis and, possibly, therapy.
 ...
PMID:In vitro and in vivo regulation of tumor antigen expression by human recombinant interferons. 190 1

Sera were collected from 111 patients diagnosed with adenocarcinoma or nonadenocarcinoma malignancies who received different schedules of interferon (IFN)-gamma or IFN-beta ser alone or in combination. Serum carcinoembryonic antigen (CEA) and tumor-associated glycoprotein-72 (TAG-72) antigen levels were measured to determine whether interferon could enhance the tumor shedding and, thereby, the serum level of either tumor antigen. Less than 10% of the sera samples from patients diagnosed with nonadenocarcinoma malignancies (e.g., hairy cell leukemia, melanoma) had positive titers of TAG-72 or CEA, and interferon neither increased nor resulted in the appearance of either tumor antigen in those sera. In contrast, 59.2% and 75.4% of the patients with adenocarcinoma had positive serum levels of TAG-72 and CEA, respectively, prior to interferon. IFN-gamma and IFN-beta ser alone or in combination significantly increased serum TAG-72 or CEA in approximately 65% of those patients. The results suggest that interferon administration to patients with adenocarcinoma can result in increased serum levels of selected tumor-associated antigens used in the diagnosis of malignancy. These preliminary findings may be important in the development of new strategies to obtain more sensitive tumor antigen serum assays for the diagnosis and monitoring for disease progression of adenocarcinoma.
 ...
PMID:Evidence for the elevation of serum carcinoembryonic antigen and tumor-associated glycoprotein-72 levels in patients administered interferons. 190 81


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>