Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The murine skin multistage carcinogenesis model was used to characterize the co-promoting and tumor progressing activities of i.p. administered recombinant DNA-derived murine gamma interferon (rMuIFN-gamma). The dorsal skins of female SENCAR mice were topically initiated with 7,12-dimethylbenz[a]anthracene (DMBA) and promoted twice a week for 20 weeks with 1 microgram of 12-O-tetradecanoylphorbol-13-acetate (TPA). Doses of rMuIFN-gamma that had no effect on papilloma multiplicities when administered 1 day prior to TPA treatment increased the numbers of papillomas per mouse by 33-38% when administered immediately prior (zero time) to TPA application. A minimum of 6 weeks of co-treatment with TPA and rMuIFN-gamma (zero time) were necessary for demonstration of rMuIFN-gamma-dependent co-promotion. The ad libitum administration of either 0.25 or 1% (w/v) solutions of alpha-difluoromethylornithine (DFMO) in the drinking water inhibited by 90% the TPA-dependent elevation of epidermal ornithine decarboxylase activity but had minimal effect on papilloma multiplicities in TPA-promoted mice. However, both doses of DFMO completely suppressed rMuIFN-gamma-dependent co-promotion. Carcinoma incidence and multiplicities by weeks 46-48 of the promotion-progression period were statistically indistinguishable for initiated mice treated with TPA, TPA + DFMO, TPA + IFN-gamma or TPA + DFMO + IFN-gamma. Similarly, i.p. administration of rMuIFN-gamma to papilloma-bearing mice in a tumor progression study, with and without simultaneous topical TPA treatment, did not affect carcinoma latency or carcinoma multiplicities. C57BL/6 mice initiated with DMBA developed few papillomas (0.2 paps/mouse) after 19 weeks of TPA promotion. The i.p. administration of rMuIFN-gamma to C57BL/6 mice at the time of TPA treatment, at doses that were co-promoting in SENCAR mice, did not increase papilloma multiplicities. Collectively, our studies suggest that the co-promoting activity of rMuIFN-gamma is exceptionally sensitive to inhibition by DFMO and dependent upon the scheduling and duration of rMuIFN-gamma treatment, and the mouse strain/stock employed for the studies.
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PMID:Modulation of the co-promoting activity of gamma interferon in SENCAR and C57BL/6 mouse skin by difluoromethylornithine and the scheduling and duration of interferon treatment. 210 81

Ornithine decarboxylase (ODC) activity was measured in colon adenocarcinomas and adjacent normal-appearing colon mucosa from a total of 40 patients undergoing surgical resections. The enzyme activity was measured in the presence and absence of GTP, since recent work has demonstrated a GTP-activatable form of ODC in some murine and human tumors. In general, ODC specific activity was higher in adenocarcinomas than in adjacent normal-appearing mucosa. Of greater interest, however, was the finding that 13 of 40 tumors and 3 of 40 mucosae contained a GTP-activatable form of ODC. These are minimal estimates of the proportion of tissues positive for this enzyme form, since a multiple sampling protocol indicated that expression of a GTP-activatable ODC was not uniform throughout a given tumor. Chromatographic analyses of tumor extracts revealed the presence in some tumors of multiple size forms of ODC, only some of which were activated by GTP. Enzyme kinetic data indicated that the multiple forms of ODC can have different affinities for L-ornithine and that GTP can "normalize" the aberrant kinetic properties of these forms. While there was no statistically significant correlation of the presence of a GTP-activatable ODC with stage of disease, analysis of our data revealed a positive association of a GTP-activatable ODC with tumor site; a much higher percentage of tumors of the cecum contained this ODC isoform than tumors of other colonic segments (64% versus less than or equal to 25% for other sites). These results demonstrate (a) the presence of a functionally distinct form of ODC in some human colon adenocarcinomas and (b) a distinct regional distribution of this ODC form within the colon. We suggest this alteration in a key enzyme in the growth-associated pathway of polyamine biosynthesis may play a role in colon tumor progression.
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PMID:Properties of ornithine decarboxylase in human colorectal adenocarcinomas. 231 97

In vivo effects of DL-alpha-difluoromethylornithine (DFMO) on the metabolism of polyamines and nucleotide phosphates were monitored in P388/S leukemia cells grown intraperitoneally in BDF1 inbred male mice. Inhibiting the ornithine decarboxylase (ODC) activity DFMO depleted putrescine and spermidine to 30-50 and 50-60%, respectively, and increased spermine to 25-60% compared with the controls, when given as 2% solution in drinking water of the tumor-bearing animals. DFMO treatment caused a parallel 56% elevation of total nucleotide content in tumor cells with distinct and significant increase of some nucleotide phosphates. The most pronounced alterations were shown in the intracellular UTP (202%), CTP (103%), ADP (92%) and ATP (71%) concentrations. Changes in polyamine and nucleotide phosphate metabolisms were dependent on tumor progression. A possible explanation of the metabolic events induced by DFMO is discussed.
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PMID:In vivo effects of DL-alpha-difluoromethylornithine on the polyamine and nucleotide phosphate metabolism in P388/S leukemia cells. 308 89

Prostate cells of human and rat origin produce polyamines in high content, whose apparent functions relate to cellular proliferation and secretory activities. Formation is dependent on the enzyme ornithine decarboxylase (ODC) which is irreversibly inhibited by alpha-difluoromethylornithine (DFMO). It has been postulated that pretreatment with DFMO may render cells more susceptible to subsequent chemotherapy. Copenhagen X Fischer F1 rats bearing the Dunning R3327 MAT-LyLu prostatic adenocarcinoma were given DFMO or adriamycin (ADR), alone or in combination. Those receiving DFMO were continuously provided the drug ad libitum, in water (2.5%), for the duration of the experiment, beginning 2 days prior to ADR administration. At intervals, tumor sizes were measured, animal survivals noted and comparisons made to nontreated, tumor-bearing controls. The results indicate that ADR alone or in combination with DFMO significantly reduced tumor progression, but that only combination therapy significantly prolonged survivals. Decreased tumor progression produced by DFMO alone was not statistically significant. Differences produced with combined use were additive and suggest that DFMO may augment ADR chemotherapy.
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PMID:Combination therapy using polyamine synthesis inhibitor alpha-difluoromethylornithine and adriamycin in treatment of rats carrying the Dunning R3327 MAT-LyLu prostatic adenocarcinoma. 311 12

We previously demonstrated that repeated intravesical instillation of DFMO, an irreversible inhibitor of ornithine decarboxylase, inhibits (or retards) urinary bladder carcinogenesis in rats. The present investigation was conducted to determine if high intraluminal concentration of DFMO alters initiation by MNU and to determine if DFMO inhibition is due to arrest of tumor progression or simply retardation of the tumor development. Results showed that the inhibitory effects demonstrated by DFMO treatment during the early phase of study disappeared as the observation period was extended. Failure to suppress tumor development might be due to failure to control intracellular polyamine levels below the critical level and this failure in turn might be due to the rapid fall of intravesical DFMO concentration following instillation.
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PMID:Effects of alpha-difluoromethylornithine on initiation and promotion of urinary bladder carcinogenesis in a heterotopically transplanted rat urinary bladder. 313 75

Topical treatment of mouse skin with the potent tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) results in an array of biochemical alterations, one of the earliest being a more than 200-fold transient induction of epidermal ornithine decarboxylase (ODC) activity. There is an excellent correlation between the induction of epidermal ODC activity and changes in the level of immunoreactive ODC protein following a single TPA treatment to skin. Both ODC activity and protein levels peak at 4.5 h after TPA treatment and rapidly fall to basal levels by 24 h. Cycloheximide treatment of mice in which ODC had been previously induced by TPA indicated a similar rapid turnover of both ODC catalytic activity and protein levels. Northern blot analysis of polyadenylated RNA isolated from mouse epidermis after a single TPA treatment revealed the stimulation of one species of ODC mRNA of 2.0 kilobases with a maximum at 3.5 h declining by 16 h. The same-sized species of ODC mRNA was detected 4.5 h after multiple biweekly treatments with TPA as well as in mouse papillomas and carcinomas not treated with TPA for at least 1 week. Southern blot analysis of EcoRI or BamHI digests of DNA derived from mouse liver, papillomas, or carcinomas revealed no ODC gene amplification or rearrangement during neoplastic progression. These observations indicate that the induction of epidermal ODC activity following TPA treatment results in a transient increase in the steady state levels of ODC mRNA and in the rate of synthesis of ODC protein, in contrast to epidermal tumors where the levels of ODC mRNA and protein are constitutively elevated.
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PMID:Regulation of ornithine decarboxylase gene expression in mouse epidermis and epidermal tumors during two-stage tumorigenesis. 381 31

The indication of ornithine decarboxylase (ODC) by barbiturates and the ability of barbiturates to enhance neoplastic progression of chemically initiated cancer was examined in rat liver. All seven barbiturates induced ODC with barbital (7.7 fold increase) and phenobarbital (5.7 fold increase) demonstrating the most potent activity. Maximum induction of ODC by phenobarbital was obtained in 18 h. Barbital (500-5000 p.p.m.) and phenobarbital (500 p.p.m.) administered in the drinking water enhanced the appearance of diethylnitrosamine (DENA)-initiated gamma- glutamyltranspeptidase (GGTase)-positive foci. Amobarbital, hexabarbital and pentabarbital did not enhance the appearance of GGTase-positive foci. In the absence of previous initiation by DENA, the enhancing regimen of the barbiturates did not cause the appearance of GGTase-positive foci. Barbiturates induced ODC activity in rat liver and enhanced the incidence of DENA initiated GGTase-positive foci.
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PMID:Comparison of enhancement of GGTase-positive foci and induction of ornithine decarboxylase in rat liver by barbiturates. 612 34

Vitamin B6 metabolism has been investigated in several highly and well-differentiated Morris hepatomas. Comparisons have been made with two poorly differentiated Morris hepatomas, with host livers obtained from tumor-bearing animals, and with fetal, neonatal, and adult rat liver. The pyridoxal phosphate content and the activities of pyridoxine kinase and pyridoxine phosphate oxidase of all Morris hepatomas examined were significantly less than those in adult host or control livers and generally fell in the range determined for fetal and neonatal liver. A similar pattern was not evident for the activity of pyridoxine phosphate phosphatase. Relative to control and host livers, the activity in hepatomas of the pyridoxal phosphate (PLP)-dependent enzyme, ornithine decarboxylase, was generally elevated. Dexamethasone, at a dose which caused an elevation in the activity of PLP-dependent tumor tyrosine aminotransferase, had no effect on PLP metabolism. The data indicate that tumor progression in the Morris hepatoma spectrum in relation to vitamin b6 metabolism falls into an onco-developmental pattern characterized by a diminished amount of tissue PLP and a diminished capability to metabolize precursor vitamer forms to PLP.
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PMID:Vitamin B6 metabolism in liver and liver-derived tumors. 612 59

The progression of normal Syrian hamster embryo cells to a neoplastic phenotype after treatment with a chemical carcinogen and continuous exposure to phorbol ester tumor promoters was studied in cell culture. Tumor promoters were able to rescue cell lines derived from individual carcinogen-treated colonies from a program of cellular senescence. In general, these cell lines did not grow in soft-agar medium or produce tumors in newborn hamsters at early passages but acquired these properties at later passages. These cell lines were used to study the temporal acquisition of a phenotypic characteristic of neoplastic rather than normal hamster embryo cells: the synergistic induction of the enzyme ornithine decarboxylase (ODC) by tumor promoter and serum growth factors (O'Brien, T. G., Saladik, D., and Diamond, L. Regulation of polyamine biosynthesis in normal and transformed hamster cells in culture. Biochim. Biophys. Acta, 632: 270, 1980). All cell lines that acquired neoplastic status with passage in culture exhibited the synergistic induction of ODC prior to their acquisition of the ability to either grow in soft-agar medium or produce tumors in newborn hamsters. Cell lines that responded to promoters with the synergistic induction of ODC accumulated greater levels of polyamines, especially putrescine, after promoter treatment than did normal cells. Tumor promoters did not affect the percentage of cells labeled with [3H]thymidine in preneoplastic cell lines, a finding similar to previous results in normal and neoplastic hamster cells. These studies demonstrate that tumor promoters can affect the early stages of neoplastic progression in carcinogen-treated Syrian hamster embryo cells and that a particular phenotypic property found in neoplastic hamster cells, the synergistic induction of ODC by tumor promoters and serum growth factors, is acquired by cell lines before they acquire neoplastic potential.
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PMID:Effects of tumor-promoting phorbol diesters on neoplastic progression of Syrian hamster embryo cells. 705 99

Overexpression of p185erbB2/neu has been detected in many adenocarcinomas, including prostatic cancer. In this study, a nontumorigenic cell line isolated from the rat prostatic epithelium (NbE) transfected with the activated oncogene p185neu-T was used to investigate the role of this oncogene in tumor progression. When clones overexpressing p185neu-T were injected orthotopically (1.5 to 2 x 10(6) cells) into the dorsal-lateral prostates of nude mice, prostatic tumors were detected in all mice injected and metastasis to the skeletal muscle in the rib area in 60-80% of the mice injected. Tumor and metastasis origin was confirmed by reselection with G418 and reverse transcriptase-polymerase chain reaction. Control cell lines produced no prostatic tumors or metastases. Incubation at low density (12500 cells/2 cm2) in serum-free medium revealed that clones overexpressing p185neu-T had a higher rate of [3H]thymidine incorporation than did control clones on 3, 5, and 7 d after plating (P < or = 0.0001) and constitutively overexpressed the 2.6-kb ornithine decarboxylase transcript. Additionally, clones overexpressing p185neu-T demonstrated an increased expression of epidermal growth factor receptor and p180erbB4, as judged by RNA blot analysis. Together these data support the hypothesis that overexpression of p185neu-T fosters tumor progression by several pathways, including induction of the metastatic cascade, increased proliferative capabilities, and increased expression of other members of the erbB2 gene family.
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PMID:Metastasis induced by overexpression of p185neu-T after orthotopic injection into a prostatic epithelial cell line (NbE). 925 83


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