Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

New inhibitors of the enzyme thymidylate synthase (TS) are now reaching clinical application. Alteration of the dUTP: dTTP ratio may be critical to TS inhibition-induced tumor cell death. The DNA polymerase assay with modification was used to rapidly and sensitively measure dUTP, dTTP, and dUTP:dTTP ratios in cell extracts of HT29 human colon carcinoma cells treated with the specific TS inhibitor ZD1694 [N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid]. These results revealed an increase in the dUTP:dTTP ratio at 2 hr after a 2-hr exposure to ZD1694 at concentrations of 0.05 to 0.2 microM with significant normalization at 16 hr after a 2-hr exposure despite evidence of continued TS inhibition. This assay is highly sensitive and reproducible for levels of dUTP and is less labor intensive than traditional assays.
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PMID:Measurement of deoxyuridine triphosphate and thymidine triphosphate in the extracts of thymidylate synthase-inhibited cells using a modified DNA polymerase assay. 933 81

Neuroblastomas frequently show spontaneous regression and differentiation, which may at least partly be regulated by signaling through nerve growth factor and its receptors, TRK-A and p75LNTR. We studied 52 neuroblastic tumors to test whether the cell death-related proteases, interleukin-1 beta converting enzyme (ICE), CPP32, and Ich-1, were involved in the regression of the tumors. High levels of expression of ICE and CPP32 were significantly correlated with a high level of TRK-A expression, single copy of N-myc, younger age, lower stages, and better prognosis. The immunohistochemical studies and Western analyses as well as the terminal dUTP-biotin nick end labeling (TUNEL) method revealed that both ICE and CPP32 were translocated from the cytoplasm into the nuclei in regressing, apoptotic tumor cells. Our results suggest that ICE and CPP32 cysteine proteases may play an important role in regulating the apoptotic process of the favorable neuroblastomas.
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PMID:High levels of expression and nuclear localization of interleukin-1 beta converting enzyme (ICE) and CPP32 in favorable human neuroblastomas. 937 72

Uracil can arise in DNA by misincorporation of dUTP into nascent DNA and/or by cytosine deamination in established DNA. Based on recent findings, both pathways appear to be promoted in the methyl-deficient model of hepatocarcinogenesis. A chronic increase in the ratio dUTP:dTTP with folate/methyl deficiency can result in a futile cycle of excision and reiterative uracil misincorporation leading to premutagenic apyrimidinic (AP) sites, DNA strand breaks, DNA fragmentation and apoptotic cell death. The progressive accumulation of unmethylated cytosines with chronic methyl deficiency will increase the potential for cytosine deamination to uracil and further stress uracil mismatch repair mechanisms. Uracil is removed by a highly specific uracil-DNA glycosylase (UDG) leaving an AP site that is subsequently repaired by sequential action of AP endonuclease, 5'-phosphodiesterase, a DNA polymerase and DNA ligase. Since the DNA polymerases cannot distinguish between dUTP and dTTP, an increase in dUTP:dTTP ratio will promote uracil misincorporation during both DNA replication and repair synthesis. The misincorporation of uracil for thymine (5-methyluracil) may constitute a genetically significant form of DNA hypomethylation distinct from cytosine hypomethylation. In the present study a significant increase in the level of uracil in liver DNA as early as 3 weeks after initiation of folate/methyl deficiency was accompanied by parallel increases in DNA strand breaks, AP sites and increased levels of AP endonuclease mRNA. In addition, uracil was also detected within the p53 gene sequence using UDG PCR techniques. Increased levels of uracil in DNA implies that the capacity for uracil base excision repair is exceeded with chronic folate/methyl deficiency. It is possible that enzyme-induced extrahelical bases, AP sites and DNA strand breaks interact to negatively affect the stability of the DNA helix and stress the structural limits of permissible uracil base excision repair activity. Thus substitution of uracil for thymine induces repair-related premutagenic lesions and a novel form of DNA hypomethylation that may relate to tumor promotion in the methyl-deficient model of hepatocarcinogenesis.
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PMID:Presence and consequence of uracil in preneoplastic DNA from folate/methyl-deficient rats. 939 4

Apoptosis and cell proliferation play important roles in the cellular response to chemotherapy, and may have prognostic value. The percentage of apoptotic cells [apoptotic index (AI)] was evaluated in ovarian carcinomas of 25 patients by the terminal desoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL) technique. All patients were surgically treated and received postoperatively chemotherapy consisting of cytoxan and cisplatin or carboplatin. As a marker of proliferation the mRNA expression of histone H3 in tumor tissue was determined. In addition, tumor vascularity was assessed by immunohistochemistry and factor VIII. Patients with high AI had significantly shorter survival times (p=0. 0001) or recurrence-free intervals (p=0.004) than patients with low AI. No significant relationship was found between AI and histone H3 mRNA expression, however, an inverse correlation of AI with microvessel density was detected. Tumors with high AI had significantly lower microvessel count than tumors with low AI (p=0. 002). The obtained data suggest that AI can be predictive of treatment outcome in ovarian cancer.
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PMID:Spontaneous apoptosis in ovarian cancer: an unfavorable prognostic factor. 945 61

In this study, we investigated whether fluorescein isothiocyanate (FITC)-labeling of test DNA and Texas-red (TR) labeling of reference DNA in comparative genomic hybridization (CGH) experiments cause the results to differ from those obtained using the opposite combination (reverse labeling). Analysis was performed on a total of 20 DNA specimens consisting of 13 frozen bone marrow aspirates from patients with acute myeloid leukemia, and fresh peripheral blood samples from seven healthy donors. For CGH, one aliquot from each test DNA sample was labeled using nick-translation with FITC-dUTP and another with TR-dUTP. Afterwards, the FITC-dUTP and TR-dUTP-labeled test DNAs were hybridized to TR-dUTP- and FITC-dUTP-labeled normal reference DNAs, respectively. The results using the two combinations were compared with each other and with the results of G-banding karyotype analysis. Karyotype data was used to detect artifacts known to occur in some chromosome regions in CGH analysis. The control DNAs labeled with FITC or TR showed no DNA copy number changes. Regardless of the fluorochrome employed for labeling, no DNA copy number changes were detected using CGH in patients with normal karyotypes, nor in patients whose karyotype aberrations were present in less than 40% of cells. In the remaining patients, CGH revealed DNA copy number changes that coincided with the results of the G-banding analysis. Hybridization artifacts known to occur in CGH experiments affecting chromosome regions 1p33-pter, 16p, 17p, 19, and 22 were observed in 15-23% of the tumor samples labeled with FITC, but not in samples labeled with TR. In addition, other previously unreported overrepresentations affecting 7q21, 9q34, 16q, 17q, and chromosome 20 were observed at very low frequencies in up to 10% of the samples when FITC was used to label test DNA. However, when TR was used, overrepresentations were observed at 4q13-q21, 11q21-q23, 13q21-qter, and Xq21-q22, whereas 19p was underrepresented. The results demonstrate that TR-labeling confirms abnormalities detected using FITC-labeling and reduces hybridization artifacts in the known problematic regions of the human genome.
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PMID:Comparison of fluorescein isothiocyanate- and Texas red-conjugated nucleotides for direct labeling in comparative genomic hybridization. 951 16

The pharmacodynamics of doxorubicin in human prostate tumors were studied using histocultures of radical prostatectomy specimens. Drug treatment lasted 96 h. The antiproliferative effect was measured by the inhibition of DNA precursor ([3H]thymidine) incorporation, and the cytotoxic effect was measured by monitoring cells with fragmented DNA, as indicated by the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay. The average [3H]thymidine labeling index in 17 tumors was 39% (range, 20-56%). The antiproliferative and cytotoxic effects were concentration dependent and reached 100% at 6 and 17 microM doxorubicin. The cytotoxic concentrations were significantly higher than the antiproliferative concentrations, indicating that prostate tumors were more sensitive to the antiproliferative effect than they were to the cytotoxic effect of doxorubicin. The antiproliferative effect was inversely correlated with patient's age (P < 0.02) and weakly correlated with LI and Gleason grade (P = 0.07 and 0.06, respectively), but it was not correlated with clinical stage, prostate-specific antigen secretion, or race of patients (P > 0.12). In contrast, the cytotoxic effect was positively correlated with Gleason grade (P < 0.05) and weakly correlated with stage (P < 0.08), but it was not correlated with the other parameters (P > 0.18). The opposite correlations between the two effects with tumor grade suggest that the two effects are not coupled. A comparison of the drug concentrations required to produce 50% antiproliferative (0.06 microM) and cytotoxic (2 microM) effects and the literature data on plasma drug concentrations derived from systemic treatment suggest that there are minimal drug effects at the clinically achievable drug concentrations and that regional delivery of doxorubicin to the prostate may be necessary to provide adequate concentrations to produce antiproliferative and cytotoxic effects.
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PMID:Pharmacodynamics of doxorubicin in human prostate tumors. 951 11

We investigated the occurrence of apoptotic cell death in 104 colorectal carcinomas by terminal-deoxynucleotidyl-transferase-mediated dUTP-diotin nick end-labeling (TUNEL) to determine whether apoptosis could be a useful prognostic factor. The apoptotic index (AI) was calculated as the percentage of positive cancer cells per 1,000 cancer cells, the median AI being 4.1, with a range of 1.9-4.7. Apoptosis was less frequently observed in tumors with higher malignant potential, such as those at advanced stages Dukes B, C and D, than those at Dukes stage A (P < 0.05); in tumors showing evidence of moderate differentiation than in well-differentiated tumors (P < 0.05); and in tumors with venous invasion or lymph node metastasis than in those without these features (P < 0.05). Moreover, the subgroup of patients with a low AI of < 4.1 had a significantly poorer survival rate than the subgroup with a high AI in tumors at Dukes stage C, the 5-year survival rates being 33% vs 68% (P < 0.05; Cox-Mantel). Our findings suggest that less apoptosis might result in a greater progression of colorectal carcinoma, and that the rate of apoptosis might be an indicator of the degree of malignancy. Thus it would appear that the frequency of apoptosis in tumor cells could be a useful prognostic factor in colorectal carcinoma.
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PMID:Apoptosis as a prognostic factor in colorectal carcinoma. 952 2

To cast light on the mechanisms of drug-resistance, experimental brain tumors were immunohistochemically evaluated for expression of glutathione S-transferase (GST)-alpha, mu, pi, p-glycoprotein and apoptosis-related factors, such as bcl-2 and p53, as well as by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL) method. Rat brain tumors induced by means of prenatal exposure to ethylnitrosourea (ENU) were treated with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and/or vincristine. Tumors more than 2 mm in size were considered to be drug resistant. The expression of GST-mu was strongly positive in ACNU-treated brain tumors, while p-glycoprotein was overexpressed in vincristine-treated brain tumors. Neither p53 nor bcl-2 expression directly correlated with apoptosis identified by TUNEL method, but tumors lacking apoptotic cells always demonstrated the expression of either GST-mu or p-glycoprotein. These results indicate that tumors resistant to chemotherapy might not be susceptible to induction of apoptosis, and therefore that mechanisms of drug resistance are related to programmed cell death in brain tumors.
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PMID:Drug resistance and apoptosis in ENU-induced rat brain tumors treated with anti-cancer drugs. 952 10

The use of interleukin 2 (IL-2) as an antineoplastic agent has been limited by the serious toxicities that accompany the doses necessary for a tumor response. Elevation of nitric oxide (NO) and tumor necrosis factor (TNF) both have been implicated in IL-2 toxicities. CNI-1493, a tetravalent guanylhydrazone, is an inhibitor of macrophage activation including the synthesis of TNF and other cytokines. Doses of CNI-1493 as low as 1 mg/kg/day conferred complete protection against fatal toxicity of IL-2 with IL-2 doses tenfold higher than the safely tolerated level in Sprague-Dawley rats. Moreover, typical pathologic changes in the lungs, kidneys, and the liver caused by IL-2 infusion were blocked by cotreatment with CNI-1493. When animals bearing established hepatomas were given IL-2 and CNI-1493 combination therapy, 10 of 10 hepatomas regressed from 1 cm3 to <1 mm3. Intracytoplasmic TNF levels were increased in normal tissues from IL-2 treated animals, and treatment with CNI-1493 maintained TNF at control levels. The degree of apoptosis measured by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling staining of tumors following IL-2 therapy was not reduced compared with IL-2 cotreated with CNI-1493. In contrast, apoptosis in the liver and lung parenchyma following IL-2 therapy was blocked completely by cotreatment with CNI-1493. Taken together, these data showed that low and infrequent doses of CNI-1493 markedly protected animals from IL-2 systemic toxicities whereas not affecting tumor response to IL-2 therapy. With the protection afforded by CNI-1493 treatment, IL-2 therapy dose levels could be increased to provide significant antitumor effects in animals with established hepatomas.
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PMID:The tetravalent guanylhydrazone CNI-1493 blocks the toxic effects of interleukin-2 without diminishing antitumor efficacy. 953 77

We examined cell loss (apoptosis) and proliferation in a histopathological spectrum of epidermal squamous cell neoplasia, including 11 cases of solar keratosis (SK), 18 Bowen's diseases (BD) and 19 invasive squamous cell carcinomas (SCC). Apoptotic and proliferative cells were determined by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-digoxigenin nick end labeling (TUNEL) and by the detection of nuclear antigen Ki-67, respectively. Few apoptotic cells were observed in normal epidermis, while TUNEL index (TI; percentage of TUNEL-positive cells) was highest for SCCs, followed by BDs and SKs, in the order given. Although the mean Ki-67 index did not differ between SCCs and BDs, both disease types showed a significantly higher index than the SKs. Of SCCs, both TI and Ki-67 index values were significantly higher in poorly than in well differentiated carcinomas. TI was significantly higher in SCCs without P53 immunohistochemical expression than in SCCs with P53 expression, while TI and Ki-67 indices did not correlate with P53 expression in the SKs and BDs. These results suggest that apoptosis reflects not only cell loss, but also proliferative activity in the epidermal neoplastic lesions.
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PMID:Apoptosis and cellular proliferation in human epidermal squamous cell neoplasia. 955 Mar 11


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