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)

The reactivity of normal and tumor host lymphocytes incubated with normal serum or with serum or malignant ascites fluid from tumor hosts was measured by the ability of the lymphocytes to synthesize ornithine decarboxylase after phytohemagglutinin stimulation. Each of three tumors tested (a solid fibrosarcoma, an ascites mammary carcinoma, and an ascites ovarian carcinoma) caused increasing unresponsiveness in the lymphocytes of mice with progressing syngeneic neoplastic growth. The sera and particularly the malignant ascites fluids from mice given implants of the ascites cancers became progressively inhibitory to the activation of lymphocytes from tumor hosts as well as from normal mice. The serum from mice carrying s.c. implants of the fibrosarcoma enhanced the activation of lymphocytes from tumor hosts and from normal mice during early tumor growth before it also became inhibitory.
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PMID:Effect of progressive neoplastic growth on the decarboxylation of DL-[1-14C]ornithine by lymphocytes from C3H/He tumor hosts. 66 20

1. Ehrlich ascites-carcinoma cells contained relatively high concentrations of spermidine and spermine, but the putrescine content of the washed cells was less than 10% of that of higher polyamines. 2. Ascites-tumour cells likewise exhibited high activities of L-ornithine decarboxylase (EC 4.1.1.17), S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50), spermidine synthase (EC 2.5.1.16) and spermine synthase. 3. During the first days after the inoculation, the polyamine pattern of the ascites cells was characterized by a high molar ratio of spermidine to spermine, which markedly decreased on aging of the cells. 4. Various diamines injected into mice bearing ascites cells rapidly and powerfully decreased ornithine decarboxylase activity in the carcinoma cells, apparently through a mechanism that was not a direct inhibition of the enzyme in vitro. Cadaverine (1,5-diaminopentane) and 1,6-diaminohexane were the most potent inhibitors of ornithine decarboxylase among the amines tested. 5. Chronic treatment of the mice with diamines resulted in a virtually complete disappearance of ornithine decarboxylase activity, and after 24h a significant decline in spermidine accumulation. 6. Cadaverine appeared to be an especially suitable compound for use as an inhibitor of the synthesis of higher polyamines, at least in Ehrlich ascites cells, since this diamine also acted as a competitive inhibitor for putrescine in the spermidine synthase reaction without being incorporated into the higher polyamines.
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PMID:Polyamines and their biosynthetic enzymes in Ehrlich ascites-carcinoma cells. Modification of tumour polyamine pattern by diamines. 90 22

The polyamines are normal cell constituents considered to have an important role in the regulation of proliferation and differentiation. DFMO is an irreversible, enzyme-activated, suicide inhibitor of ornithine decarboxylase (ODC), the enzyme responsible for the first and rate-limiting step in mammalian polyamine synthesis. Preliminary data show that DFMO inhibits tumor cell growth in vitro and in vivo, and that it demonstrates chemopreventive activity in a variety of animal tumors. The prostate contains some of the highest concentrations of polyamines and of polyamine-synthetic enzymes (including ODC) in the mammalian organism. ODC activity in the prostate was shown to be more susceptible to DFMO inhibition than in other organs. We have found the ODC activity of the Dunning R3327 rat prostatic carcinomas to be as sensitive to inhibition by DFMO as the normal rat prostate. Furthermore, DFMO was inhibitory to the growth of the tumor both in vitro and in vivo. Given the slow growth rate and long latency period of human prostate cancer and the preliminary DFMO data, we suggest that clinical trials to evaluate the chemopreventive potential of DFMO in prostatic carcinoma deserve serious consideration.
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PMID:Chemoprevention in prostate cancer: the role of difluoromethylornithine (DFMO). 128 67

Transcription of the ornithine decarboxylase (ODC) gene is rapidly elevated by activation of protein kinase A (PKA). The additive influence of three cis-acting elements is responsible for this regulation in an adrenal carcinoma cell line. Two sites, CRE2 at -48 base pairs (bp) relative to the start of transcription and CRE3 at +95 bp, are identical to the core motif of the cAMP-responsive element (CRE) of the somatostatin gene and are conserved in the mouse, rat, and human ODC genes. Mutation of CRE2 resulted in a substantial decrease in basal promoter activity, as well as a 5-fold decrease in inducibility of the ODC promoter by PKA. CRE3 did not contribute to the basal activity of the ODC promoter, but mutation of this site resulted in a 2-fold decrease in inducibility by PKA. Deletion of a 45-bp sequence (GC-box) located 5' of CRE2, also resulted in a 2-fold decrease in inducibility of the ODC promoter. DNase I protection revealed the presence of protein binding at CRE2, the TATA box, and the GC-box of the ODC promoter. Mutation of CRE2 resulted in loss of protection of this sequence, as well as the 3' extension of the footprint over the TATA box, without affecting interactions at the GC box. Antibodies to the well characterized CRE-binding protein CREB recognized proteins binding to CRE2, suggesting that binding of CREB, or an antigenically related protein, is important for the activity of CRE2. Additionally, recombinant CREB bound to a DNA probe containing the CRE2 sequence.
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PMID:Multiple DNA elements responsible for transcriptional regulation of the ornithine decarboxylase gene by protein kinase A. 135 8

Tumorigenesis requires increased biosynthesis of polyamines and elevated levels of ornithine decarboxylase, which is the rate-limiting enzyme in the polyamine synthesis pathway. Previous animal studies have noted a marked increase in ornithine decarboxylase after exposure to tumorigenic stimuli and that pretreatment with vitamins A and E provides protection against the carcinogenic action. However, studies of ornithine decarboxylase activity in human oral cavity carcinoma have not been as specific. The goal of this study was to determine whether a specific difference in ornithine decarboxylase activity occurs in tumor versus adjacent normal tissue in head and neck squamous cell carcinoma patients. Ornithine decarboxylase activity was measured in 30 consecutive head and neck cancer patients undergoing surgical therapy. Ornithine decarboxylase levels were found to be significantly elevated in tumor tissue samples when compared to adjacent normal mucosa samples (P less than .004). This finding confirms the previous findings noted in animal models and implies that the protective effects of vitamins A and E will extend to human head and neck cancers.
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PMID:Ornithine decarboxylase activity in tumor and normal tissue of head and neck cancer patients. 149 49

The term biologic marker (biomarker) of colorectal cancer refers in this article to an early preclinical phenotypic characteristic that relates to the risk for developing this cancer. Putative biologic markers in the normal colorectal mucosa of patients at risk include abnormal cell proliferation as determined by kinetic studies, ornithine decarboxylase activity, and polyamine synthesis. Alterations of mucin synthesis have been studied using both histochemical stains and lectin-binding techniques. Blood group and related carbohydrate antigens also have been evaluated as potential biomarkers in the normal mucosa. Biopsy small (less than 5 mm) polyps encountered at endoscopy has become a standard practice. Although a small polyp found to be an adenoma has a low likelihood of harboring high-grade dysplasia or invasive carcinoma, it represents an indicator of risk for colorectal neoplasia. Hyperplastic polyps, however, even though they have certain epidemiologic associations with colorectal neoplasia, are controversial as putative biomarkers of clinical relevance. Current research supports a concept of a field defect of the colorectal mucosa at risk for neoplasia, which may be identified by phenotypic abnormalities of the normal mucosa and the development of small adenomas.
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PMID:Precursors of colorectal carcinoma. Biopsy and biologic markers. 151 79

Methylglyoxal bis(guanylhydrazone) (MGBG) has been studied clinically as an antitumor and antileukemic agent and is recognized as a potent but nonspecific inhibitor of the key polyamine biosynthetic enzyme, S-adenosylmethionine decarboxylase (SAMDC). A series of four SAMDC inhibitors with structural features similar to MGBG have been found to have improved potency and specificity toward the target enzyme, SAMDC. Relative to MGBG, the new derivatives were much more effective in inhibiting partially purified preparations of SAMDC (50% inhibitory concentration, 10 to 100 nM), much less effective at inhibiting diamine oxidase, and inactive toward ornithine decarboxylase. The inhibitors varied relative to MGBG in their ability to compete with spermidine for uptake, with two being similar and two being less effective. Against L1210 leukemic cells and T24 bladder carcinoma cells, the compounds were slightly less effective than MGBG at inhibiting cell growth, with 50% inhibitory concentration values of 1 to 10 microM as compared with 0.5 and 1.1 microM, respectively, for MGBG. Under 50% growth-inhibitory conditions, the inhibitors decreased SAMDC activity, increased ornithine decarboxylase activity and putrescine pools, and markedly depleted spermidine and spermine pools of L1210 cells. At the same time, mitochondrial integrity as assessed by whole-cell pyruvate oxidation and mitochondrial DNA content was not affected as it was with MGBG. At doses less than one tenth that of the maximally tolerated dose, all of the new inhibitors strongly suppressed the growth of B16 melanoma in vivo with minimal weight loss or toxicity. At doses less than one sixth the maximally tolerated dose, they effectively inhibited the growth of T24 human bladder carcinoma xenografts. In these same systems, MGBG showed only marginal antitumor activity. These studies identify two potent and efficacious inhibitors of SAMDC as potential antitumor agents and reaffirm the importance of SAMDC as a target in anticancer drug discovery.
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PMID:New S-adenosylmethionine decarboxylase inhibitors with potent antitumor activity. 151 37

Ornithine decarboxylase (ODC) activity, which seems to increase in premalignant lesions, was studied in gallbladder mucosa from 32 patients with or without anomalous arrangement of the pancreaticobiliary duct (AAPBD). Mucosal ODC activity was significantly increased in 17 patients with AAPBD compared with 15 control subjects with normal biliary anatomy. Among the 17 patients with AAPBD, ODC activity was significantly increased in 7 in whom the major pancreatic duct joined the common bile duct (P-C type) compared with 8 in whom the common bile duct joined the pancreatic duct (C-P type). The increased ODC activity in gallbladder mucosa suggests that patients with the P-C type of AAPBD may have an increased risk of gallbladder cancer. These results are consistent with recent clinicopathologic studies of AAPBD that have demonstrated an association between AAPBD and biliary tract malignancy. Determination of the mechanism that induces mucosal ODC activity may provide a clue to the pathogenesis of gallbladder carcinoma in patients with AAPBD.
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PMID:Gallbladder mucosa ornithine decarboxylase activity is increased in patients with anomalous arrangement of the pancreaticobiliary duct. 156 66

1-Amino-3-(aminooxy)-2-propanol (6a) has been synthesized and found to inhibit rat liver ornithine decarboxylase (ODC) with an IC50 in the nanomolar range. Compound 6a served as a basis for the design of new enzyme inhibitors, which led to the identification of 3-(aminooxy)-2-fluoropropanamine (15) as a new powerful enzyme blocker. Compound 15 inhibited ODC at 3 times lower concentrations than 6a and 3-(aminooxy)propanamine (APA), and it was superior to APA as an antiproliferative agent in inhibiting the growth of human T24 bladder carcinoma cells in vitro.
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PMID:2-substituted 3-(aminooxy)propanamines as inhibitors of ornithine decarboxylase: synthesis and biological activity. 157 31

The effects of 5-fluorouracil (FUra) treatment on thymidine kinase (TKase) activity were examined in vivo in CD8F1 mice bearing first generation CD8F1 mouse mammary tumors. TKase activity was not affected by low dose FUra25 (25 mg/kg), a dose which substantially inhibited thymidylate synthase (TSase), but was severely inhibited 24 hr following treatment with FUra100, a weekly maximally tolerated dose, as judged by activity measurements and labeling of DNA with [3H]thymidine. The amount of (FU)RNA was increased markedly with increasing FUra dose from 0.4 nmol/mg DNA at FUra25 to 2.2 nmol/mg DNA at FUra100. At FUra100, TKase activity gradually declined over 24 hr to less than 10% of the control value, remained low for a further 48 hr, and then was gradually restored to control levels by 168 hr. The loss of TKase activity followed the incorporation of FUra into RNA which peaked at 4-5 hr. TKase activity was not restored by removal of endogenous inhibitors but was restored by treatment with uridine. TKase activity was not inhibited by therapeutic levels of methotrexate (300 mg/kg). TKase from murine colon 38 carcinoma was also severely inhibited, but the activity from colon 26 was only partially (50%) inhibited. Ornithine decarboxylase was also inhibited by FUra100 treatment in the CD8F1 tumor. These results demonstrate that certain short-lived, proliferation-related enzymes are affected by FUra doses higher than those required for TSase inhibition, and this effect appears to correlate with incorporation of FUra into RNA. Thus, in some tumors high doses of FUra can inhibit salvage as well as de novo synthesis of thymidylate providing an increased block of DNA synthesis and increased therapeutic advantage.
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PMID:Loss of murine tumor thymidine kinase activity in vivo following 5-fluorouracil (FUra) treatment by incorporation of FUra into RNA. 172 9


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