Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007097 (carcinoma)
 152,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To further understand the molecular mechanisms and the biological indicators of colonic tumorigenesis, the authors examined tyrosine kinase activity in the cytosol and in the particulate fraction of the homogenates of specimens from 20 human colonic carcinomas and compared them with the adjacent normal mucosal tissues. Total protein tyrosine kinase activity could be precisely detected using miniphosphocellulose column purification and a synthetic peptide, Glu-asparagine (Asp)-alanine (Ala)-Glu-tyrosine (Tyr)-Ala-Ala-arginine (Arg)-Arg-Arg-glycine (Gly) (E11-G1), as an artificial substrate. Tyrosine kinase activity of colonic carcinoma and normal mucosa was reduced in the cytosol fraction whereas activity in the particulate fraction was elevated with respect to protein concentration. The average specific activity ratios were 1.95 +/- 0.27 (normal cytosolic/carcinoma cytosolic) and 0.57 +/- 0.01 (normal particulate/carcinoma particulate) for tyrosine kinase activity. Cellular distribution (% cytosol) of tyrosine kinase activity in normal mucosa and in carcinoma varied from 21.0% to 91.2% and from 7.0% to 61.4%, respectively. In nearly all cases the percentage of cytosolic tyrosine kinase activity in carcinoma tissues was lower than in normal tissues. There was no difference due to histologic type or the presence of adenomatous components. A significant decrease of cytosolic tyrosine kinases was correlated with Dukes' Stage A. With advancing Dukes' stage, the average specific activity ratios (normal cytosol/carcinoma cytosol) were decreased. This study indicates that colonic carcinogenesis might be associated with alterations in cellular levels of tyrosine kinase activity and that the average specific activity ratio (normal cytosol/carcinoma cytosol) had a possible correlation with colonic tumor growth.
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PMID:Altered protein tyrosine kinase levels in human colon carcinoma. 198 53

Forty-four male and female subjects aged 22-57 years were studied. Thirteen patients had acute viral hepatitis, and eleven patients had cholestatic jaundice due to carcinoma of the head of the pancreas. Twenty healthy volunteers who served as controls were also included. In hepatitis patients, the mean plasma levels of total cholesterol (TC) and the high density lipoprotein (HDL)-phospholipid/phospholipid (HDLPL/PL) ratio were reduced, and HDL-cholesterol (HDLC), HDL-phospholipid (HDLPL) and the phospholipid/total cholesterol (PL/TC) ratio were normal, while total phospholipid (PL) levels and the HDLC/TC ratio were significantly increased compared to the control values. In patients with cholestatic jaundice the mean plasma total cholesterol, phospholipid and HDLC levels were elevated, and HDLPL/PL, HDLPL, HDLC/TC and PL/TC remained normal compared to the control values. A comparison within the patient groups showed that plasma TC, PL and HDLC levels were significantly increased in cholestatic jaundice when compared with the corresponding levels in hepatitis patients. The mean plasma levels of HDLPL, HDLC/TC and PL/TC did not show any significant variation within the patient groups. Alkaline phosphatase (ALP) correlated positively with TC, and total protein correlated negatively with TC and HDLPL, while albumin correlated negatively with TC, HDLC and HDLPL in cholestatic jaundice. Alanine amino-transferase (ALAT) also correlated positively with PL in cholestatic jaundice, while albumin correlated positively with TC in hepatitis. The results suggest that lipoproteins might be metabolized differently in these two forms of cholestasis.
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PMID:Changes in plasma high density lipoprotein cholesterol and phospholipid in acute viral hepatitis and cholestatic jaundice. 199 58

This article gives a comprehensive survey on the anticancer activity of nitrosoureas linked to steroidal androgens in methylnitrosourea (MMU)-induced rat mammary carcinoma. cis-Androsterone, testosterone, 19-nortestosterone and 5-alpha-dihydrotestosterone were used as carrier hormones and were linked to various cytotoxic N-[N'-(2-chloroethyl)-N'-nitrosocarbamoyl] (CNC)-aminoacids and to N-(2-hydroxyethyl)-N'-(2-chloroethyl)-N'-nitrosourea hemisuccinate (HECNU-hemisuccinate). In the MNU-model used esters of dihydrotestosterone (DHT) invariably were more active and less toxic than those of testosterone, nortestosterone and cis-androsterone. Within the DHT esters of CNC-aminoacids those of CNC-glycine, CNC-methionine and CNC-alanine showed the highest antineoplastic activities and superiority compared with equimolar dosages of their unlinked mixtures. Additionally, CNC-alanine-DHT ester had the highest therapeutic ratio of all agents investigated. HECNU-hemisuccinate-DHT ester, on the other hand, achieved even higher antitumor activity at the optimal dose but had a narrower therapeutic ratio. No obvious correlation between antineoplastic efficacy and receptor binding affinity could be demonstrated, but, to be active, a conjugate apparently had to have some receptor binding affinity for both androgen and progesterone receptors. The results obtained indicate that linking antineoplastic agents to transport molecules with affinity to steroid receptors is a highly promising approach to obtain drugs with specific activity in steroid receptor containing tumors.
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PMID:Androgen-linked alkylating agents: biological activity in methylnitrosourea-induced rat mammary carcinoma. 225 72

Spent culture medium from the human pancreatic carcinoma cell line HPC-YP, which can propagate in a protein-free, chemically defined medium without any other supplements, was analyzed for the presence of the cysteine protease, cathepsin L. The secreted form of cathepsin L was distinguished from the lysosomal form by its increased stability at alkaline pH, by its strong thermostability, and by its larger molecular size. HPC-YP cathepsin L was still stable at pH 7.4 and at 56 degrees C after 60-min preincubation. The molecular weight of this enzyme was estimated to be 68,000, compared with a molecular weight of 29,000 for normal liver cathepsin L. By Western blot analysis, HPC-YP enzyme was found to be composed of two components, one with a molecular weight of 37,000 and the other of 31,000. This result suggests that HPC-YP enzyme in the spent medium may be a complex of the proenzyme (in the case of liver proenzyme; Mr 39,000) and the mature enzyme (in the case of liver mature enzyme; Mr 29,000). Interestingly, an intrinsic inhibitor was also separated from the spent medium by gel filtration. The molecular weight of this inhibitor was estimated to be approximately 13,000. The cathepsin L of HPC-YP proved more resistant toward leupeptin than did liver cathepsin L. On the other hand, the former was more sensitive than the latter toward the diazomethane inhibitors, Z-Phe-Phe-CHN2 and Z-Phe-Ala-CHN2. These results indicate that cathepsin L secreted from cancer cell lines may play a role in the destruction of basal lamina, invasion of tissue, and formation of metastasis.
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PMID:Characterization of a cathepsin L-like enzyme secreted from human pancreatic cancer cell line HPC-YP. 229 6

Acivicin is an investigational amino acid antitumor antibiotic currently being evaluated in Phase II clinical trials. In humans acivicin causes reversible, dose-limiting central nervous system (CNS) effects including somnolence, ataxia, personality changes, and hallucinations. We have observed and reported previously that acivicin-treated cats exhibit symptoms (ataxia, sedation, somnolence) resembling CNS toxicity reported in humans. We hypothesized that if acivicin uptake into brain were mediated by a saturable transport system common to endogenous amino acids, drug uptake and CNS toxicity might be blocked by elevation of normal amino acid concentrations in circulating plasma. To test this hypothesis, cats received constant-rate i.v. infusions of either saline or Aminosyn, 10% (a commercially available mixture of 16 amino acids not containing glutamine, glutamate, aspartate, or cysteine) for 4 h prior to and 18 h subsequent to administration of acivicin at a dose producing marked behavioral changes in control cats. Presence or absence of ataxia and sedation were noted at intervals after acivicin treatment. Results showed that Aminosyn infusion prevented CNS symptoms in six of eight cats. Subsequent experiments showed that acivicin levels in brain tissue of Aminosyn-treated cats were 13% of the drug levels in saline-infused cats. Acivicin levels in most peripheral tissues were also decreased significantly by Aminosyn infusion but not to the extent observed in brain. Decreased brain uptake was shown to be due to a combination of amino acid blockade of drug transport into that organ and of increased total body clearance of drug. Concomitant Aminosyn treatment did not alter the efficacy of acivicin in mice bearing L1210 leukemia or MX-1 human mammary carcinoma. Further studies demonstrated that a solution containing only four large neutral amino acids (leucine, isoleucine, phenylalanine, and valine) could also protect cats from acivicin-induced CNS toxicity, apparently without increasing acivicin total body clearance. However, a mixture of several other amino acids contained in Aminosyn (alanine, arginine, tyrosine, histidine, proline, serine, and glycine) failed to prevent CNS toxicity. We conclude that cotreatment with Aminosyn or a mixture of large neutral amino acids could protect cancer patients from acivicin-induced CNS toxicity without ablating antitumor efficacy.
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PMID:Prevention of central nervous system toxicity of the antitumor antibiotic acivicin by concomitant infusion of an amino acid mixture. 238 52

This study concentrated on the influence of 2-chloroethylnitrosocarbamoyl-L-alanine (CNC-L-ala) linked to oestradiol (CNA-L-ala-E2) or dihydrotestosterone (CNC-L-ala-DHT) in position 17 of the respective steroid hormone on tumour growth and receptor kinetics of methylnitrosourea-induced rat mammary carcinoma. Both compounds almost completely arrested logarithmically growing mammary carcinoma of Sprague-Dawley rats: in the first week CNC-L-ala-E2 blocked the growth of these tumours by 92% compared to untreated control animals while, in animals treated with the physically equimolar mixture of CNC-L-ala and oestradiol (positive control), tumour growth was inhibited by 51% only. CNC-L-ala-DHT arrested the tumour growth in the first week by 95%, while the respective positive control (CNC-L-ala plus dihydrotestosterone) effected a growth inhibition of 71% compared to the untreated control. These results correlate well with the influence of both drugs on the cytosolic receptor content of sexual steroid hormones in the tumours. CNC-L-ala-E2 depleted the content of oestradiol receptors and kept it down for a week, while concomitantly the content of progesterone receptors increased considerably and that of androgen receptors showed a short-lived decrease. CNC-L-ala-DHT depleted androgen receptors as well as progesterone receptors. The content of androgen receptors remained low for a week, while that of progesterone receptors recovered within 8 days. The content of oestrogen receptors showed a moderate decrease.
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PMID:Modulation of cytosolic sexual steroid receptors in autochthonous methylnitrosourea-induced rat mammary carcinoma following application of 2-chloroethylnitrosocarbamoyl-L-alanine linked to oestradiol or dihydrotestosterone. 239 Apr 81

A 2-fold increase in hepatic alanine concentration was observed in rats bearing a Walker 256 carcinoma growing sub-cutaneously. Decreases were observed in the activities of both cytosolic and mitochondrial isozyme forms of L-alanine-2-oxoglutarate aminotransferase. Activities of two enzymes involved in a secondary pathway of haem synthesis involving alanine, L-alanine-4,5-dioxovalerate aminotransferase and the NADP-requiring isozyme form of 4-oxo-5-hydroxyvalerate dehydrogenase were also reduced but there was no change in liver porphyrin concentration. L-alanine-glyoxalate aminotransferase activity was unaffected. The results are discussed in relation to the utilisation of alanine as a gluconeogenic substrate in the tumor-bearing host.
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PMID:Increased liver alanine in the tumour-bearing host. Altered levels of some enzymes involved in alanine metabolism. 240 67

The monoclonal antibody (MAb) DF3 reacts with a high molecular weight glycoprotein detectable in human breast carcinomas and human milk. The present studies have analyzed the structure of DF3 protein produced by human BT-20 and MCF-7 breast carcinoma cells. The size of the DF3 core protein was determined by glycosidase digestion of purified DF3 glycoprotein and by immunoprecipitation after [3H]proline labeling. A core protein size of approximately Mr 160,000 was obtained for DF3 protein in BT-20 cells. In contrast, two DF3 proteins of approximately Mr 160,000 and 230,000 were detectable in MCF-7 cells. Amino acid analysis indicated that DF3 antigen from these cells is relatively rich in threonine, serine, proline, glycine, and alanine. The results also demonstrate that the DF3 epitope resides on the core protein, although reactivity with MAb DF3 was affected by the presence of carbohydrate. Finally, using synthetic peptides, we demonstrate that the DF3 epitope is present within the 20 amino acids encoded by the tandem repeat recently identified from our sequence analysis of a DF3 complimentary DNA.
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PMID:Structural analysis of the DF3 human breast carcinoma-associated protein. 247 Apr 98

Antibodies to rheumatoid arthritis nuclear antigen (RANA) are four- to sixfold increased in sera from patients with rheumatoid arthritis (RA), whereas levels of antibodies to other EBV encoded antigens are slightly elevated or normal. We have demonstrated that the major epitopes recognised by anti-RANA antibodies are represented by a synthetic peptide, P62, corresponding to part of the internal repeat sequence which contains only the amino acids glycine and alanine. In an enzyme-linked immunosorbent assay, anti-P62 antibodies in rheumatoid arthritis sera were four fold higher than healthy and disease controls. By contrast, levels of antibodies to a cloned fusion protein, representing the C-terminus of EBNA-1 and excluding the IR3 region, were normal in RA, but elevated fivefold in nasopharyngeal carcinoma (NPC). Affinity purified anti-P62 antibodies reacted with EBNA-1 and RANA but also with a 60 kD protein present in tissue extracts which has been tentatively identified as cytokeratin. This suggests that the specific increase of anti-P62 antibodies in RA may be due to cross-reactions with autoantibodies to structural proteins with repeat sequences containing glycine. Such sequences are found in cytokeratin and proteoglycans, suggesting that anti-P62 (and hence anti-RANA) antibodies may be cross-reactive antibodies of pathogenic significance in RA, though not necessarily indicating an aetiological role for EBV.
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PMID:Antibodies in rheumatoid arthritis react specifically with the glycine alanine repeat sequence of Epstein-Barr nuclear antigen-1. 248 75

In vitro activity of 1-(2-chloroethyl)-1-nitrosocarbamoyl-L-alanine-oestradiol-17-ester (CNC-ala-17-E2) at three concentrations in transplanted MXT mammary carcinoma in mice and autochthonous methylnitrosourea (MNU)-induced mammary carcinoma in Sprague-Dawley rats, as well as in 30 human primary breast carcinomas using the bilayer soft agar assay is described. Eighty-five percent of MXT tumours showed a more than 70% inhibition of colony formation in response to CNC-ala-17-E2. The MNU-induced model did not show this high degree of inhibition; only 5% of tumours showed an inhibition of up to 70%, but a superiority of the hormone-linked agent over the unlinked single agents was nevertheless discernible. By contrast, in human breast carcinomas there was no statistically superior response to the hormone-linked preparation as opposed to the single agents. Thus, in MXT mammary carcinoma the in vitro results parallelled previous findings in vivo, whereas in the MNU-induced autochthonous tumour model this close in vivo-in vitro correlation was not observed. The discrepancy between in vivo and in vitro results found in the autochthonous rat model indicates that hormone-linked nitrosoureas should not necessarily be abandoned for the treatment of human breast carcinoma on the basis of negative in vitro results alone.
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PMID:[In vitro study of estradiol-linked nitrosourea in breast cancers in the mouse, rat and human: interspecies comparison]. 253 70


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