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)

Doxorubicin, pirarubicin, and FAD-104, but not aclarubicin or MX 2, flattened the morphology of NIH3T3 cells that had been transformed by human H-ras and K-ras. The effect appeared on almost all cells, as early as 2 d following exposure to the antibiotics at concentrations inhibiting cell growth by 50% or more. The morphological alteration accompanied other normal cell phenotypes, such as the restoration of actin stress fibers, anchorage dependence of cell growth and an increase in nucleoside diphosphate (NDP) kinase activity. NIH3T3 cells transformed by src and other tumor cell lines responded less prominently, if at all.
 ...
PMID:Distinct effects of clinically used anthracycline antibiotics on ras oncogene-expressed cells. 750 87

Quinone reductase [NAD(P)H:(quinone acceptor) oxidoreductase, EC 1.6.99.2], also called DT diaphorase, is a homodimeric FAD-containing enzyme that catalyzes obligatory NAD(P)H-dependent two-electron reductions of quinones and protects cells against the toxic and neoplastic effects of free radicals and reactive oxygen species arising from one-electron reductions. These two-electron reductions participate in the reductive bioactivation of cancer chemotherapeutic agents such as mitomycin C in tumor cells. Thus, surprisingly, the same enzymatic reaction that protects normal cells activates cytotoxic drugs used in cancer chemotherapy. The 2.1-A crystal structure of rat liver quinone reductase reveals that the folding of a portion of each monomer is similar to that of flavodoxin, a bacterial FMN-containing protein. Two additional portions of the polypeptide chains are involved in dimerization and in formation of the two identical catalytic sites to which both monomers contribute. The crystallographic structures of two FAD-containing enzyme complexes (one containing NADP+, the other containing duroquinone) suggest that direct hydride transfers from NAD(P)H to FAD and from FADH2 to the quinone [which occupies the site vacated by NAD(P)H] provide a simple rationale for the obligatory two-electron reductions involving a ping-pong mechanism.
 ...
PMID:The three-dimensional structure of NAD(P)H:quinone reductase, a flavoprotein involved in cancer chemoprotection and chemotherapy: mechanism of the two-electron reduction. 756 29

This study was to develop radiofluorinated ethyluracil (FEU) and deoxyadenosine analogues (FAD) for noninvasive assessment of tumor proliferative potential by positron emission tomography (PET). 5-(2-Fluoroethyl)uracil ([18F]FEU) was prepared by treating 2,4-dimethoxy-5-(2-hydroxyethyl)pyrimidine with K18F, followed by hydrolysis with HBr. Fluorodeoxyadenosine ([18F]FAD) was prepared by treating a triacetylated analogue of adenosine with K18F. In vitro cell proliferation assay of [18F]-FEU was performed using human peripheral blood mononucleus cells. Tissue distributions were studied in breast tumor-bearing rats at 0.5, 1, 2 and 4 h along with autoradiography at 45 min postinjection. PET imaging studies were conducted in VX-2 tumor-bearing rabbits. In vitro assay indicated that [18F]FEU incorporated into DNA/RNA during cell proliferation. Tumor-to-tissue count density ratios of [18F]FAD and [18F]-FEU increased as a function of time. [18F]FAD had higher tumor-to-nontumor tissue count density ratios than [18F]FEU. Autoradiograms of [18F]FEU and [18F]FAD, and PET images of [18F]FEU, showed that the tumors could be well visualized. The results suggest that [18F]FEU and [18F]FAD have potential use in evaluating tumor cell proliferation by PET.
 ...
PMID:Assessment of tumor cell proliferation using [18F]fluorodeoxyadenosine and[18F]fluoroethyluracil. 869 41

The overall objective was to design and evaluate biodegradable implants for local drug delivery in clinical conditions and/or diseases described below, which are currently treated with systemic administration of drugs. Local delivery of cefazolin is desired in conditions such as osteomyelitis, soft-tissue infection and for prevention of post-surgical infections. Similarly, implanting a biodegradable device loaded with taxol in the cavity created by tumor resection will provide high local concentrations of taxol killing the malignant cells which may have survived the surgery, thus preventing metastasis and regrowth of the tumor and also prevent the systemic side effects of taxol. Prolonged reversible nerve blockade required in a number of clinical situations involving acute or chronic pain such as post-surgical pain following herniorrhaphy and thoracotomy can be achieved with local delivery of bupivacaine. Therefore, disk-shaped implants of polyanhydride, P(FAD-SA, 50:50 w/w), loaded with 10% w/w of cefazolin sodium, taxol and bupivacaine were prepared and evaluated for content uniformity and in vitro release characteristics for the above mentioned local drug delivery applications. All of cefazolin sodium was released in 14 days while 90% bupivacaine was released in 35 days. In striking contrast, taxol was released very slowly, and only 15% taxol was released in 77 days. The overall release appeared to be following first order kinetics, and the initial linear profile was fitted to zero order kinetics to obtain release parameters. Since cefazolin is highly water soluble and bupivacaine is moderately water soluble, compared to taxol which is extremely lipophilic, the aqueous solubility of the incorporated drug appeared to influence in release characteristics. Very good correlation was observed between release parameters (Ao, ko) and the solubility and intrinsic dissolution rate (IDR) of drugs suggesting that the hydrophilic/hydrophobic nature of the drug influences its release from polyanhydride devices. Since polyanhydrides are believed to undergo pure surface erosion, release of the incorporated drug should be independent of its physicochemical properties, however the results presented in this study suggest otherwise. Therefore, P(FAD-SA, 50:50 w/w) may not be undergoing surface erosion, and the diffusion and dissolution properties of the drug in addition to erosion characteristics of the polyanhydride appear to play a role in drug release. Implants prepared and evaluated in this study released cefazolin, bupivacaine and taxol for a prolonged duration of time; however, depending upon the desired duration of release, an appropriate polyanhydride will have to be selected. For example, taxol was released so slowly that a more hydrophilic polyanhydride may have to be selected to release all the drug in a shorter period of time to be of any therapeutic use. Cefazolin implants released the drug for a sufficient duration for osteomyelitis and soft-tissue infection but the release was more prolonged than required for prevention of post-surgical wound infection.
 ...
PMID:Biodegradable polyanhydride devices of cefazolin sodium, bupivacaine, and taxol for local drug delivery: preparation, and kinetics and mechanism of in vitro release. 968 48

Glutathione reductase (GR) is a chemotherapeutic target. Murine GRcDNA, which contains 85% GC in the 38 codons following the start codon, was assembled from the PCR-amplified exon 1 and a downstream cDNA prior to expression in Escherichia coli as a His(6)-tagged protein. Recombinant GR, an FAD-containing homodimer, corresponds in its enzymic and spectral properties to GR isolated from murine Ehrlich ascites tumor cells. Another cDNA, representing GR with a mitochondrial targeting sequence, yielded two distinct enzymically active expression products.
 ...
PMID:Assembly and functional expression of murine glutathione reductase cDNA: a sequence missing in expressed sequence tag libraries. 1056 26

Fluorescence spectroscopy has the potential to improve the in vivo detection of intraepithelial neoplasias; however, the presence of inflammation can sometimes result in misclassifications. Inflammation is a common and important pathologic condition of epithelial tissues that can exist alone or in combination with neoplasia. It has not only been associated with the presence of cancer but also with the initiation of cancer by damage induced due to the oxidative activity of inflammatory cells. Microscopic examination of cervical biopsies has shown increased numbers of polymorphonuclear and mononuclear leukocytes in inflamed tissues mostly confined to the stroma. The purpose of this study was to characterize the fluorescence properties of human polymorpho- and mononuclear leukocytes and compare their fluorescence to that of cervical cancer cells. Human neutrophils were purified from peripheral blood and their fluorescence characterized over an excitation range of 250-550 nm. There are four notable excitation emission maxima: the tryptophan peak at 290 nm excitation, 330 nm emission; the NAD(P)H peak at 350 nm excitation, 450 nm emission, the FAD peak at 450 nm excitation, 530 nm emission and an unidentified peak at 500 nm excitation, 530 nm emission. Treatment of these peripheral blood neutrophils with 40 nM phorbol myristate acetate or with the chemotactic peptide formyl-Met-Leu Phe (1 M) demonstrated a significant increase in NAD(P)H fluorescence. Isolated mononuclear cells have similar emission peaks for tryptophan and NAD(P)H and a small broad peak at 450 nm excitation, 530 nm emission suggestive of FAD. Comparison of the fluorescence from leukocytes to epithelial cancer cell fluorescence has demonstrated the presence of these fluorophores in different quantities per cell. The most notable difference is the high level of tryptophan in cervical epithelial cancer cells, thus offering the potential for discrimination of inflammation.
 ...
PMID:Characterization of the autofluorescence of polymorphonuclear leukocytes, mononuclear leukocytes and cervical epithelial cancer cells for improved spectroscopic discrimination of inflammation from dysplasia. 1073 51

Spermine is a constituent of all vertebrate cells. Nevertheless, it exerts toxic effects if it accumulates in cells. Spermine is a natural substrate of the FAD-dependent polyamine oxidase, a constitutive enzyme of many cell types. It has been reported that the toxicity of spermine was enhanced if polyamine oxidase was inhibited. We were interested to examine spermine toxicity to human colon carcinoma-derived CaCo-2 cells because, in contrast to most tumor cell lines, CaCo-2 cells undergo differentiation, which is paralleled by changes in polyamine metabolism. CaCo-2 cells were remarkably resistant to spermine accumulation, presumably because spermine is degraded by polyamine oxidase at a rate sufficient to provide spermidine for the maintenance of growth. Inactivation of polyamine oxidase increased the sensitivity to spermine. A major reason for the enhanced spermine cytotoxicity at low polyamine oxidase activity is presumably the profound depletion of spermidine, and the consequent occupation of spermidine binding sites by spermine. Hydrogen peroxide and the aldehydes 3-aminopropanal and 3-acetamidopropanal, the products of polyamine oxidase-catalyzed splitting of spermine and N1-acetylspermine, contribute little to spermine cytotoxicity. Activation of caspase by spermine was insignificant, and the formation of DNA ladders, another indicator of apoptotic cell death, could not be observed. Thus it appears that cell death due to excessive accumulation of spermine in CaCo-2 cells was mainly nonapoptotic. The content of brush border membranes did not change between days 6 and 8 after seeding, and it was not affected by exposure of the cells to spermine. However, the activities of alkaline phosphatase, sucrase, and aminopeptidase in nontreated cells were considerably enhanced during this period, but remained low if cells were exposed to spermine. These changes appear to indicate that differentiation is prevented by intoxication with spermine, although other explanations cannot be excluded.
 ...
PMID:Spermine cytotoxicity to human colon carcinoma-derived cells (CaCo-2). 1091 67

NAD(P)H:quinone oxidoreductase type 1 (QR1, NQO1, formerly DT-diaphorase; EC 1.6.99.2) is an FAD-containing enzyme that catalyzes the nicotinamide nucleotide-dependent reduction of quinones, quinoneimines, azo dyes, and nitro groups. Animal cells are protected by QR1 from the toxic and neoplastic effects of quinones and other electrophiles. Alternatively, in tumor cells QR can activate a number of cancer chemotherapeutic agents such as mitomycins and aziridylbenzoquinones. Thus, the same enzyme that protects the organism from the deleterious effects of quinones can activate cytotoxic chemotherapeutic prodrugs and cause cancer cell death. The catalytic mechanism of QR includes an important initial step in which FAD is reduced by NAD(P)H. The unfavorable charge separation that results must be stabilized by the protein. The details of this charge stabilization step are inaccessible to easy experimental verification but can be studied by quantum chemistry methods. Here we report ab initio quantum mechanical calculations in and around the active site of the enzyme that provide information about the fine details of the contribution of the protein to the stabilization of the reduced flavin. The results show that (1) protein interactions provide approximately 2 kcal/mol to stabilize the planar conformation of the reduced flavin isoalloxazine ring observed in the X-ray structure; (2) the charge separation present in the reduced planar form of the flavin is stabilized by interactions with groups of the protein; (3) even after stabilization, the reduction potential of the cofactor remains more negative than that of the free flavin, making it a better reductant for a larger variety of quinones; and (4) the more negative reduction potential may also result in faster kinetics for the quinone reduction step.
 ...
PMID:Mechanism of NAD(P)H:quinone reductase: Ab initio studies of reduced flavin. 1134 Jun 59

gp91phox is the catalytic subunit of the respiratory burst oxidase, an NADPH-dependent, superoxide generating enzyme present in phagocytes. In phagocytes, the enzyme functions in host defense, but reactive oxygen generation has also been described in a variety of non-phagocytic cells, including cancer cells. We previously reported the cloning of Nox1 (NADPH oxidase1), a homolog of gp91phox, its expression in colon and vascular smooth muscle, and its oncogenic properties when overexpressed [Suh et al. (1999). Nature 401, 79-82]. Herein, we report the cloning and tissue expression of three additional homologs of gp91phox, termed Nox3, Nox4 and Nox5, members of a growing family of gp91phox homologs. All are predicted to encode proteins of around 65 kDa, and like gp91phox, all show 5-6 conserved predicted transmembrane alpha-helices containing putative heme binding regions as well as a flavoprotein homology domain containing predicted binding sites for both FAD and NADPH. Nox3 is expressed primarily in fetal tissues, and Nox4 is expressed in not only fetal tissues, but also kidney, placenta and glioblastoma cells. Nox5 is expressed in a variety of fetal tissues as well as in adult spleen and uterus. Nox isoforms are aberrantly expressed in several cells derived from human cancers, with Nox4 being the isoform most frequently expressed in the tumor cells investigated. Thus, expression of Nox family members is likely to account for some of the reactive oxygen generation seen in non-phagocytic cells.
 ...
PMID:Homologs of gp91phox: cloning and tissue expression of Nox3, Nox4, and Nox5. 1137 45

The antitrypanosomal and antitumour activities of (2,2':6',2"-terpyridine)platinum(II) complexes have been postulated to be due to their ability to inhibit irreversibly the NADPH/FAD redox enzymes trypanothione reductase and human thioredoxin reductase respectively. Here we show that these platinum(II) complexes metallate recombinant human albumin (rHA) at the single free thiol group (Cys-34). Moreover, the (2,2':6',2"-terpyridine)platinum(II) complex can be transferred from rHA to other thiols, such as 2-hydroxyethanethiol or glutathione. Human serum albumin could therefore provide a natural transport mechanism for the selective delivery of these agents to tumor cells by the enhanced permeability and retention (EPR) mechanism.
 ...
PMID:Transfer of 4'-chloro-2,2':6',2"-terpyridine platinum(II) between human serum albumin, glutathione and other thiolate ligands. A possible selective natural transport mechanism for the delivery of platinum(II) drugs to tumour cells. 1171 36


<< Previous 1 2 3 4 5 6 7 Next >>