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)

Reactive oxidants generated by phagocytes are of central importance in host defenses, tumor surveillance, and inflammation. One important pathway involves the generation of potent halogenating agents by the myeloperoxidase-hydrogen peroxide-chloride system. The chlorinating intermediate in these reactions is generally believed to be HOCl or its conjugate base, ClO-. However, HOCl is also in equilibrium with Cl2, raising the possibility that Cl2 executes oxidation/ halogenation reactions that have previously been attributed to HOCl/ClO-. In this study gas chromatography-mass spectrometric analysis of head space gas revealed that the complete myeloperoxidase-hydrogen peroxide-chloride system generated Cl2. In vitro studies demonstrated that chlorination of the aromatic ring of free L-tyrosine was mediated by Cl2 and not by HOCl/ClO-. Thus, 3-chlorotyrosine serves as a specific marker for Cl2-dependent oxidation of free L-tyrosine. Phagocytosis of L-tyrosine encapsulated in immunoglobulin- and complement-coated sheep red blood cells resulted in the generation of 3-chlorotyrosine. Moreover, activation of human neutrophils adherent to a L-tyrosine coated glass surface also stimulated 3-chlorotyrosine formation. Thus, in two independent models of phagocytosis human neutrophils convert L-tyrosine to 3-chlorotyrosine, indicating that a Cl2-like oxidant is generated in the phagolysosome. In both models, synthesis of 3-chlorotyrosine was inhibited by heme poisons and the peroxide scavenger catalase, implicating the myeloperoxidase-hydrogen peroxide system in the reaction. Collectively, these results demonstrate that myeloperoxidase generates Cl2 and that human neutrophils use an oxidant with characteristics identical to those of Cl2 during phagocytosis. Moreover, our observations suggest that phagocytes exploit the chlorinating properties of Cl2 to execute oxidative and cytotoxic reactions at sites of inflammation and vascular disease.
 ...
PMID:Human neutrophils employ chlorine gas as an oxidant during phagocytosis. 882 92

Determination of blood tyrosinase mRNA by RT-PCR and markers of tyrosinase activity (L-DOPA/L-tyrosine ratio) by HPLC have been proposed as biological tools for the detection of metastases in melanoma patients. We prospectively evaluated their significance and clinical value in a group of 30 stage III (n = 10) and IV (n = 20) melanoma patients and one with melanosis of Dubreuilh. L-DOPA/L-tyrosine ratio was elevated in 30% of stage III, 41% of stage IV patients (range: 7.5-261.0 x 10(5)) and in melanosis of Dubreuilh (184.8) (reference values: 6-16 X 10(5)). One stage III and four stage IV melanoma patients were positive for tyrosinase mRNA. In stage IV patients, tyrosinase mRNA positivity was associated with disease progression (P<0.01). The presence of tyrosinase mRNA in blood is more related to clinical status than level of melanin precursors, which probably reflects tumor burden.
 ...
PMID:Simultaneous analysis of tyrosinase mRNA and markers of tyrosinase activity in the blood of patients with metastatic melanoma. 1034 Apr 38

Few studies have been conducted focusing on a potential role of reactive oxygen species in tumor cell metabolism. Here we studied human colorectal adenocarcinomas and adenomas to determine whether oxidative stress is imposed on cancer cells in vivo and used specific antibodies against 8-hydroxy-2'-deoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal (HNE)-modified proteins, and 3-nitro-L-tyrosine (3-NT) to determine whether there is an association between oxidative stress and cellular proliferation. Higher levels of oxidative modifications in DNA and proteins were observed in carcinoma cells, but not in adenoma cells, than in the corresponding nontumorous epithelial cells by immunohistochemistry as well as high-performance liquid chromatography (HPLC)-based 8-OHdG determination. The fraction of proliferating cell nuclear antigen-positive cells was proportionally associated in adenocarcinomas with the staining intensities of 8-OHdG and 3-NT. Furthermore, Western blot analysis of the proteins extracted from carcinoma cells revealed several specific proteins modified by HNE or peroxynitrite. Thus we concluded that colorectal carcinoma, but not adenoma cells, are exposed to more oxidative stress than their corresponding nontumorous epithelial cells, regardless of clinical stage and histology, and further that the oxidative stress in carcinoma cells might stimulate cellular proliferation.
 ...
PMID:Persistent oxidative stress in human colorectal carcinoma, but not in adenoma. 1046 15

Melanoma is the most agressive skin cancer in humans. The most important prognostic factors are the histological features of the tumor, while the clinical ones play a secondary role. Melanoma progression is characterized by the metastatic process which directly threatens the patients life. Unfortunately, routine imaging methods cannot estimate early enough this metastatic risk. Are biologic markers of cancer progression more efficient than those applied in everyday practice? Are they able to evaluate the metastatic risk and thus help the therapeutic strategy? In this review, we analysed the analytical and the clinical aspects of biologic markers of cutaneous melanoma currently available or in development. At the present time it is very difficult to distinguish one single marker of melanoma progression in the blood which correlates with the stage and the prognosis of melanoma. The most specific and sensitive enough are the melanoma associated antigens protein S-100, MIA (melanoma inhibiting activity) and the melanin precursors 5-S-cysteinyldopa and the ratio L-dopa/L-tyrosine. Tyrosinase mRNA remains the best target for the detection of circulating metastatic melanoma cells by RT-PCR. Simultaneous detection of several markers might be useful if they are carefully selected. Despite the progress in the field, more clinical studies should be performed for the development of new techniques or improvements of the existing ones for the follow-up of cutaneous melanoma.
 ...
PMID:[Current biological markers of cutaneous melanoma progression]. 1076 Jul 2

The aim of this study was to investigate the cellular uptake mechanisms responsible for the accumulation of 3-[(125)I]iodo-L-alpha-methyltyrosine ((125)I-3-IMT) and 2-[(125)I]iodo-L-tyrosine ((125)I-2-IT), two radiotracers for metabolic tumor imaging, using single-photon emission tomography, into U266 human myeloma cancer cells. Time course and concentration dependency of (125)I-3-IMT uptake was assessed. Kinetic parameters were calculated using an Eadie Hofstee plot. A set of competitive inhibitors of the main amino acid transport systems was used for the discrimination of the transporters responsible for the uptake of (125)I-3-IMT and (125)I-2-IT. Protein incorporation of both tracers was determined using acid precipitation. The measured maximum velocity for (125)I-3-IMT transport was 4.199 nmol per mg protein 20 s(-1), and the Michaelis constant was 107.9 microM. Addition of 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid (BCH), a competitive inhibitor of System L, reduced the influx by 39.0+/-3.3% for (125)I-3-IMT and 66.3+/-0.9% for (125)I-2-IT. The BCH-insensitive influx was further reduced by Tryptophan (Trp) by 43.8+/-3.5% for (125)I-3-IMT and 15.3+/-1.3% for (125)I-2-IT. This suggests involvement of System T transport. We measured <2% of radioactivity in the acid precipitable fractions of both tracers with no increase in time. We conclude that the influx of (125)I-3-IMT and (125)I-2-IT into U266 human myeloma cells is mediated by both System L and System T amino acid transporters. The kinetic parameters suggest that elevated plasma levels of aromatic amino acids will reduce (123)I-3-IMT uptake in myeloma patients. Both tracers do not enter protein synthesis significantly.
 ...
PMID:In vitro characterization of the influx of 3-[125I]iodo-L-alpha-methyltyrosine and 2-[125I]iodo-L-tyrosine into U266 human myeloma cells: evidence for system T transport. 1129 23

O-phospho-L-tyrosine (P-Tyr) has been reported previously to inhibit growth of several cancer cell lines at mM concentrations. In the present study, we investigated the effect of this compound on tumor cells and normal cells in combination with radiation exposure. It could be demonstrated for the first time that P-Tyr at microM concentrations protects TP53 wild-type cells against ionizing radiation (SF4 minus BBI = 0.28, SF4 plus BBI = 0.45). On the contrary, human transformed or tumor cell lines characterized by mutated or functional inactivated TP53 were not altered or increased in their radiation sensitivity (SF4 minus BBI = 0.32, SF4 plus BBI = 0.22). Treatment of wild-type TP53 cells with P-Tyr induced stabilization of TP53 within 3 and 16 hours and a subsequent increase in CDKN1A expression after treatment. Consequently, a 16-hours pretreatment of cells with P-Tyr led to a significant radioprotective effect. This was not observed in cell lines with mutated TP53, which shows no radioprotection by P-Tyr. Thus, the present data suggest that P-Tyr-mediated radioprotection is dependent on preirradiation stabilization of TP53. The results indicate that P-Tyr is a radioprotective agent that can potentially be very useful and easy to deliver for radiation protection in general and especially in radiation therapy of TP53-mutated tumors.
 ...
PMID:O-phospho-L-tyrosine protects TP53 wild-type cells against ionizing radiation. 1199 81

High uptake of [(18)F]fluoro-2-deoxy- D-glucose (FDG) by inflammatory cells is a frequent cause of false positive results in lymph node (LN) staging by positron emission tomography. Previous studies suggest that radiolabelled amino acids may be more specific markers for viable tumour tissue than FDG. The aim of this study was to investigate quantitatively the uptake of FDG, [(3)H]methyl- L-methionine (MET) and O-2-([(18)F]fluoroethyl)- L-tyrosine (FET) in tumour-infiltrated and immunologically stimulated LNs. Popliteal LNs of Balb/c and DBA/2 mice were stimulated by injection into the right posterior foot pad of mice of either streptozotocin (STZ), causing chronic lymphadenitis, or concanavalin A (Con A), resulting in acute lymphadenitis. Tumour-infiltrated popliteal LNs were induced by inoculation of 2x10(5) lacZ-tagged T cell mouse lymphoma cells into the right posterior foot pad of syngeneic mice. Twenty-one days post inoculation of tumour cells or at various time points after STZ or Con A injection, mice were simultaneously injected intravenously with MET and FDG or MET and FET. After 30 min, mice were sacrificed and tracer uptake was determined in popliteal LNs. Contralateral LNs and LNs of untreated mice served as controls. Histopathological and immunohistochemical analysis demonstrated typical signs of chronic inflammation (non-specific sinus hyperplasia with macrophages) in STZ-treated animals and acute inflammatory changes (accumulation of neutrophilic granulocytes, vascular dilation, follicular hyperplasia) in Con A-treated animals. X-Gal staining confirmed the presence of tumour cells in the LNs of the injected side of tumour-inoculated mice. In the chronic lymphadenitis model, FDG uptake increased 3.0+/-0.1 fold [from 2.7+/-0.2 to 8.2+/-1.2 percent of injected dose per gram tissue (%ID/g)] and MET uptake 2.0+/-0.01 fold (from 4.5+/-0.6 to 9.2+/-1.1 %ID/g). In the acute lymphadenitis model, FDG uptake increased 3.9+/-0.3 fold (from 2.7+/-0.2 to 10.6+/-2.4 %ID/g) and MET uptake 1.9+/-0.1 fold (from 4.5+/-0.6 to 8.5+/-1.4 %ID/g). In contrast, FET uptake in both lymphadenitis models (1.0+/-0.03 and 1.2+/-0.04 fold) was not significantly different from that in controls (from 4.2+/-0.3 to 4.7+/-0.7 and to 5.1+/-0.4 %ID/g, respectively). Uptake of all three tracers in tumour-infiltrated LNs was significantly higher than that in control LNs. FDG uptake increased 2.8+/-0.15 fold (from 2.7+/-0.2 to 7.6+/-1.3%ID/g), MET uptake 1.7+/-0.11 fold (from 4.5+/-0.6 to 7.5+/-1.3 %ID/g) and FET uptake 2.4+/-0.15 fold (from 4.2+/-0.3 to 10.0+/-1.8 %ID/g). MET and FDG uptake was similar or higher in inflammatory than in tumour-infiltrated LNs ( P=0.01 and P<0.01, respectively). In contrast, uptake of FET showed no overlap between tumour-infiltrated and inflammatory LNs ( P<0.00001). In conclusion, tumour-infiltrated and inflammatory LNs could not be differentiated by means of FDG and MET uptake. FET, in contrast, proved to be a specific tracer for differentiating between tumour-infiltrated and inflammatory LNs in the murine models studied.
 ...
PMID:O-(2-[(18)F]Fluoroethyl)- L-tyrosine (FET): a tracer for differentiation of tumour from inflammation in murine lymph nodes. 1217 18

An easy-to-automate synthetic procedure and the kinetics and radiation dosimetry of O-(2-[18F]fluoroethyl)-L-tyrosine (FET), a recently developed amino acid tracer with potential applications in tumor imaging with PET, are described. FET was prepared in high radiochemical yield, 20-25% with no decay correction, and radiochemical purity of more than 95% in less than 60min synthesis time by a modified two-step procedure and manual operation. The kinetics and radiation dosimetry of FET were evaluated by using mice biodistribution data and the medical internal radiation dosimetry (MIRD) method. The bone (total) was the organ receiving the highest dose, 4.78x10(-3)mGy/MBq, and the brain and the whole body received the lowest dose, 1.6x10(-3)mGy/MBq, respectively. The effective dose was 9.0x10(-3)mSv/MBq. The data show that a 370-MBq (10mCi) injection of FET leads to an estimated effective dose of 3.3mSv and an estimated dose to the whole body of 0.6mGy. The potential radiation risks associated with this study are well within accepted limits.
 ...
PMID:Pharmacokinetics and radiation dosimetry estimation of O-(2-[18F]fluoroethyl)-L-tyrosine as oncologic PET tracer. 1257 21

a-Methyldopa sesquihydrate is used in the treatment of hypertension; over 20 million prescriptions are written annually for a -methyldopa or a-methyldopa sesquihydrate in the United States. a-Methyldopa sesquihydrate (USP grade, greater than 99% pure) was selected for study because of widespread human exposure and the lack of carcinogenicity studies on this compound. Fourteen-day, 13-week, and 2-year studies were conducted in F344/N rats and B6C3F1 mice. The chemical was administered in feed because human exposure is primarily by the oral route. Short-term studies were performed in bacteria and mammalian cells to evaluate the potential for genetic damage. Fourteen-Day and Thirteen-Week Studies: In the 14-day studies, the chemical was administered at dietary concentrations of 0 and 6,250-100,000 ppm. All rats receiving 100,000 ppm and 2/5 female rats receiving 50,000 ppm died. All mice lived until the end of the studies. Final mean body weights of dosed male rats were 14%-43% lower than that of controls, and those of dosed female rats were 9%-24% lower. Feed consumption by dosed male and female rats was reduced. Final mean body weights of dosed mice were generally within 10% of those of controls; feed consumption by dosed groups was lower than that by controls during the first week of the studies. In the 13-week studies, the chemical was administered at dietary concentrations of 0 and 3,100-50,000 ppm. Deaths occurred in 4/10 male rats, 7/10 female rats, and 2/10 female mice at 50,000 ppm and in 1/10 female rats at 25,000 ppm. Final mean body weights of dosed rats were 6%-46% lower than those of controls. Feed consumption by dosed rat groups was lower than that by controls. Final mean body weights of male mice at 25,000 and 50,000 ppm and female mice at 50,000 ppm were reduced 12%-19%. Feed consumption by dosed and control mice was comparable. Rats and mice receiving 25,000 and 50,000 ppm exhibited clinical signs of toxicity including lethargy, hyperexcitability, ocular discharge, and rough hair coats. Clinical signs of toxicity were judged to be more severe in dosed male mice than in female mice. Minimal to moderate kidney tubular cell regeneration was seen in male and female rats at 12,500, 25,000, and 50,000 ppm. Bone marrow hypoplasia occurred in male rats at 25,000 and 50,000 ppm and in female rats at 6,300 ppm and higher. Nuclear enlargement (karyomegaly) of the renal corticaltubular epithelium was observed in male and female mice administered 12,500-50,000 ppm; these kidney lesions were judged to be more severe and occurred more frequently at concentrations of 25,000 ppm and higher. Because of kidney lesions, bone marrow responses, and body weight effects at 12,500 ppm and higher and increased deaths and clinical signs at 25,000 and 50,000 ppm, dietary concentrations selected for male and female rats in the 2-year studies were 0, 3,100, and 6,300 ppm. Based on clinical signs, kidney effects, and body weight decreases at 25,000 and 50,000 ppm, dietary concentrations selected for male and female mice in the 2-year studies were 0, 6,300, and 12,500 ppm. Diets containing the chemical at these concentrations were fed to groups of 50 male and 50 female rats and 50 male and 50 female mice for 103 weeks. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed rats were generally 8%-17% lower than those of controls, and mean body weights of dosed mice were generally 5%-22% lower than those of controls throughout the studies. The average amount of a-methyldopa sesquihydrate consumed per day was approximately 110-120 or 230-240 mg/kg per day by low and high dose rats and 830-890 or 1,760-1,800 mg/kg by low and high dose mice. Survival was comparable among dosed and control groups (male rats: control, 28/50; low dose, 26/50; high dose, 27/50; female rats: 35/50; 34/50; 29/50; male mice: 44/50; 42/50; 39/50; female mice: 42/50; 40/50; 38/50). Clinical signs considered to be dose-related included fighting in male rats, irritability in male mice, and rough hair coats in female mice. Nonneoplastic and Neoplasle rats, irritability in male mice, and rough hair coats in female mice. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Several lesions of the forestomach, including edema, chronic inflammation, epithelial hyperplasia, and ulcers, were seen at low incidences in high dose rats. No forestomach neoplasms occurred. No neoplastic lesions were observed in either male or female rats which were considered related to a-methyldopa sesquihydrate exposure. Nephropathy (control, 3/50; low dose, 21/50; high dose, 32/50), karyomegaly (nuclear enlargement) of cells of the tubular epithelium (0/50; 46/50; 44/50, and cysts (2/50; 10/50; 10/50) were observed in the kidney of dosed female mice. Low incidences of tubular cell hyperplasia (0/50; 1/50; 1/50), tubular cell adenomas (0/50; 2/50; 0/50), and tubular cell adenocarcinomas (0/50; 0/50; 1/50) were observed in male mice. Tubular cell adenomas (3/2,029, 0.15&percnt;) and tubular cell adenocarcinomas (3/2,029, 0.15&percnt;)are uncommon in untreated control male B6C3F1 mice. No neoplastic lesions in female mice were considered related to a-methyldopa sesquihydrate exposure. Decreased incidences of several site-specific neoplasms were observed in dosed rats and mice; these decreases might have been due in part to decreased weight gain in dosed groups. The decreases occurred in the adrenal medulla of male rats (pheochromocytomas or malignant pheochromocytomas, combined: 21/49; 3/49; 10/50), uterus of female rats (endometrial stromal polyps: 15/50; 5/49; 1/50), liver of male and female mice (hepatocellular adenomas or carcinomas, combined-- male: 15/50; 5/50; 6/50; female: 4/50; 1/50; 0/50), and anterior pituitary gland of female mice (adenoma: 9/49; 4/40; 2/50). The incidences of malignant tumors (male: 19/50; 9/50; 8/50; female: 21/50; 16/50; 12/50) and benign or malignant tumors (combined) (male: 32/50; 15/50; 17/50; female: 33/50; 22/50; 21/50) were reduced in dosed mice. Reproductive Studies: a-Methyldopa sesquihydrate was administered to male F344/N rats in corn oil by gavage 5 days per week for 65 days at doses of 0, 50, 100, 200, or 400 mg/kg. Decreased body weight was seen in dosed animals. Male rats were mated to untreated female F344/N rats on days 57-61, necropsies were performed on days 65-67, and reproductive toxicity was measured by sperm count, sperm motility, organ weights, hormone levels, and histologic evaluation of the testis. Decreased fertility was observed in males dosed with a-methyldopa sesquihydrate at 200 and 400 mg/kg. Decreases were also seen in sperm count, sperm motility, apparent number of late spermatids, and plasma testosterone levels in males in the 200 and 400 mg/kg groups. This alteration of reproductive function in male rats was found to be reversible after a 13-week recovery period (without dosing). The decreased fertility observed after a-methyldopa sesquihydrate administration was probably due in part to the decreases in plasma testosterone levels. Genetic Toxicity: a-Methyldopa sesquihydrate was not mutagenic when tested with or without exogenous metabolic activation with a preincubation protocol in four strains of Salmonella typhimurium (TA97, TA98, TA100, or TA1535). No increase in chromosomal aberrations or sister chromatid exchanges was observed in Chinese hamsterovary (CHO) cells exposed to a-methyldopa sesquihydrate with or without S9. Audit: The data, documents, and pathology materials from the 2-year studies of a-methyldopa sesquihydrate have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of a-methyldopa sesquihydrate for male or female F344/N rats fed diets containing 3,100 or 6,300 ppm. There was equivocal evidence of carcinogenic activity of a-methyldopa sesquihydrate for male B6C3F1 mice, as shown by three dosed mice having uncommon tubular cell tumors of the kidney. There was no evidence of carcinogenic activity of a -methyldopa sesquihydrate for female B6C3F1 mice fed diets containing 6,300 or 12,500 ppm. Nonneoplastic lesions of the kidney including karyomegaly were observed in dosed female mice. Decreased incidences of several tumor types (in the adrenal gland in male rats, uterus in female rats, liver in male and female mice, and anterior pituitary gland in female mice) were considered related to a-methyldopa sesquihydrate exposure. Synonyms for a-Methyldopa or a-Methyldopa sesquihydrate: 3-hydroxy-a-methyl-L-tyrosine sesquihydrate; L-(a-MD); a-methyl-L-3,4-dihydroxyphenylalanine; L(-)-b-(3,4-dihydroxyphenyl)-a -methylalanine; L-(-)-3-(3,4-dihydroxyphenyl)-2-methylalanine; L-a-methyl-3,4-dihydroxyphenylalanine; a-methyl-b-(3,4-dihydroxyphenyl)-L-alanine; L-(-)-a-methyl-b-(3,4-dihydroxyphenyl)alanine; (-)-methyldopa; L-methyldopa; L-a-methyldopa; a-methyl-L-dopa Trade Names for a-Methyldopa or a-Methyldopa sesquihydrate: Aldomet; Aldometil; Aldomin; a-Medopa; AMD; Bayer 1440 L; Baypresol; Dopamet; Dopatec; Dopegyt; Hyperpax; Medomet; Medopren; Methoplain; MK. B51; MK-351; Presinol; Presolisin; Sedometil; Sembrina
 ...
PMID:NTP Toxicology and Carcinogenesis Studies of alpha-Methyldopa Sesquihydrate (CAS No. 41372-08-1) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1270 36

A fully automated synthesis of O-(3-[18F]fluoropropyl)-L-tyrosine (FPT), an amino acid tracer for tumor imaging with positron emission tomography, is described. FPT was prepared by a two-step reaction sequence. Direct nucleophilic fluorination substitution of [18F]fluoride with 1,3-di(4-methylphenylsulfonyloxy)propane on a quaternary 4-(4-methylpiperidinyl)pyridinium functionalized polystyrene anion exchange resin, followed by [18F]fluoro-1-(4-methylphenylsulfonyloxy)propane yielded FPT. The overall radiochemical yield with no decay correction was about 12%; the whole synthesis time was about 52 min, and the radiochemical purity was above 95%.
 ...
PMID:Fully automated synthesis of O-(3-[18F]fluoropropyl)-L-tyrosine by direct nucleophilic exchange on a quaternary 4-aminopyridinium resin. 1279 78


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