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At least 649 records · Page 36Linked to original sources
PubMed1992

Elevated DT-diaphorase activity and messenger RNA content in human non-small cell lung carcinoma: relationship to the response of lung tumor xenografts to mitomycin Cł.

The enzyme DT-diaphorase (DTD; NAD(P)H:quinone oxidoreductase, EC 1.6.99.2), is an obligate two electron reductase which catalyzes reduction of a broad range of substrates, including quinones. We report here variations in DTD concentrations among different classes of lung tumors known also to vary in their responsiveness to cytotoxic agents. Small cell lung carcinomas (SCLCs) and cell lines derived from them have the low DTD activities and mRNA content characteristic of normal human lung, whereas non-small cell lung carcinomas (NSCLCs) have greatly elevated levels. DTD activity was increased up to 80-fold in NSCLC tumors relative to normal lung and 20-35-fold in NSCLC relative to SCLC cell lines. Increased DTD activity appeared to be a function of the NSCLC phenotype rather than a result of derivation from a cell type rich in DTD, since all histological classes of NSCLC showed this phenotype. In addition, where transfection of SCLC cell lines with the v-Ha-ras protooncogene caused a transition to a NSCLC phenotype, DTD activity was also elevated. Neuroendocrine-positive cells (SCLC, carcinoids, and a few NSCLC lines) typically had far lower DTD activities than did cell lines which lacked neuroendocrine markers (most NSCLC cells and mesotheliomas). High DTD activity may be exploited in the design of drugs which undergo bioreductive activation by this enzyme. Consistent with this, xenografts derived from NSCLC cell lines with high DTD that were grown in athymic nude mice were more susceptible to the antitumor quinone, mitomycin C, than were xenografts derived from SCLC cells containing low DTD. These data provide a mechanistic basis for the rational design of more effective bioreductive antitumor agents for use against NSCLC.

Animals↗
PubMed1992

Sensitivity of resistant human tumor cell lines to tumor necrosis factor and adriamycin used in combination: correlation between down-regulation of tumor necrosis factor-messenger RNA induction and overcoming resistance.

A number of human tumor cell lines of various histological origin were examined for their sensitivity and resistance to tumor necrosis factor-alpha (TNF) and Adriamycin (ADR). Six ovarian lines, and one each of a renal, lung, and B-cell line, were tested for putative mechanisms of resistance to these agents. Cytotoxicity resulting from TNF or ADR showed no overall correlation in these lines. The combination of TNF and ADR produced enhanced cytotoxicity against these tumor lines and furthermore resulted in overcoming the resistance of TNF or ADR alone or in combination. A proposed mechanism of TNF resistance in tumor cells is the endogenous production of TNF mRNA and protein. There was a positive correlation between resistance to TNF and the constitutive production of TNF mRNA and protein. The TNF-resistant lines that did not constitutively produce TNF mRNA and protein and the three TNF-sensitive tumor lines exhibited up-regulation of their TNF mRNA in the presence of TNF or phorbol myristate acetate/ionophore, but did not secrete any detectable protein. Due to the enhanced cytotoxicity seen with the combination of TNF and ADR, the effect of this combination on the level of TNF mRNA was examined. ADR alone reduced the constitutive level of TNF mRNA and in combination with TNF reduced the level of induction produced by TNF. This down-regulation of TNF mRNA by ADR may play a role in the enhanced cytotoxicity seen with the combination of these 2 agents.

Down-Regulation↗
PubMed1992

Increased expression of human ribosomal phosphoprotein P0 messenger RNA in hepatocellular carcinoma and colon carcinoma.

To search for differentially expressed gene products in selected cancers of endodermal origin, cDNA libraries derived from mRNA in human hepatocellular carcinoma and adjacent grossly normal tissue were generated. From these parent libraries, subtracted cDNA libraries of tumor minus normal and normal minus tumor tissues were constructed. After screening these subtracted libraries by +/- hybridization, a cDNA clone that is overexpressed in hepatocellular carcinoma and encodes the human acidic ribosomal phosphoprotein P0 (P0) was identified. We then evaluated the expression of this phosphoprotein P0 in human colon carcinoma samples. Surgical specimens of primary tumors and liver metastases were examined by Northern hybridization of total RNA with one of 2 32P-labeled P0 probes. The mRNA level of the P0 was greater in primary colon carcinoma than in paired adjacent normal colonic epithelium in 36 of 38 cases; the mean tumor/normal ratio was 2.7 (range, up to 13). The tumor/normal ratio, when plotted against the Dukes' stage of disease, gave evidence for increasing P0 expression with increasing stage of colon carcinoma (P = 0.02). In all 8 cases of paired colon carcinoma metastatic to liver and 2 cases of paired primary hepatocellular carcinoma, the P0 mRNA level was greater in tumor than in adjacent normal liver tissue. The mean tumor/normal ratio was 4.0 (range, up to 11) for the colon cancers metastatic to liver and 4.2 for the primary hepatocellular carcinoma samples. These findings support a common increased expression of selected gene products in different tumors of endodermal origin and suggest that increased P0 expression, in line with certain other ribosomal proteins, may be associated with human colorectal cancer progression and biological aggressiveness.

Blotting, Northern↗
PubMed1992

Increase in gamma-glutamylcysteine synthetase activity and steady-state messenger RNA levels in melphalan-resistant DU-145 human prostate carcinoma cells expressing elevated glutathione levels.

The biochemical and molecular basis for the elevation of glutathione (GSH) levels commonly detected in many drug-resistant cells has not been elucidated. In a series of L-phenylalanine mustard-resistant human prostate carcinoma cell lines (DU-145), resistance was associated with elevated GSH levels, increased activity of gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH biosynthesis, and a marked increase in the steady-state levels of GCS-specific transcripts (4.0 and 3.2 kilobases). Loss of the resistant phenotype was accompanied by a reduction in GSH and a return of GCS activity and transcript levels to values comparable to those detected in the drug-sensitive parent cells. These data strongly implicate up-regulation of GCS activity as an important mechanism in the evolution of drug resistance associated with increased levels of intracellular GSH. The results further suggest that the ability to synthesize GSH may be more indicative of resistance than steady-state GSH levels per se.

Drug Resistance↗
PubMed1992

Levels of nm23 messenger RNA in metastatic malignant melanomas: inverse correlation to disease progression.

Data obtained in experimental murine tumors and in clinical specimens of human breast cancer have suggested that the nm23 gene may function as a metastasis suppressor gene. In this report we examined the nm23 mRNA level in tumor tissue obtained from distant metastases in 33 patients with malignant melanoma. The gene was differentially expressed in the tumors with a 20-fold range in hybridization intensities. The levels of nm23 mRNA in benign nevi obtained from 12 of the 33 patients were relatively low, with a mean value of 17% of that in the melanomas. In attempts to relate the level of nm23 expression in the tumor metastases to progression of the disease, the time from biopsy of the primary tumor to the appearance of metastases was used as a clinical end point. It was found that patients developing metastases during the first 2 years after diagnosis had significantly lower levels of tumor nm23 expression (56% of the mean value) compared to patients with less aggressive disease (164%) (P < 0.0004). In concordance with previous data the association found here between low levels of nm23 mRNA and the malignant potential of melanomas suggests that the nm23 gene may be implicated in the mechanism of disease progression in some types of human cancer.

Chromosomes, Human, Pair 17↗
PubMed1992

Measurement of gastrin and transforming growth factor alpha messenger RNA levels in colonic carcinoma cell lines by quantitative polymerase chain reaction.

A synthetic DNA template has been constructed that is suitable for the quantitation of mRNAs encoding gastrin, transforming growth factor alpha (TGF alpha), cholecystokinin, and the 78-kDa gastrin-binding protein. The template was used to measure levels of gastrin and TGF alpha mRNA in 7 colonic and 2 gastric carcinoma cell lines by the polymerase chain reaction. All lines produced detectable gastrin and TGF alpha mRNA with amounts varying between 2.1 and 540 molecules of gastrin mRNA/10(3) cells and 1.1 and 28 molecules of TGF alpha mRNA/10(3) cells. These results are consistent with the hypothesis that both gastrin and TGF alpha act as autocrine growth factors in colon carcinoma cell lines.

3T3 Cells↗
PubMed2006

Expression of human telomerase reverse transcriptase, Survivin, DD3 and PCGEM1 messenger RNA in archival prostate carcinoma tissue.

INTRODUCTION: The wide spectrum of biological behavior displayed by prostate cancer (PCa) warrants investigation of potential PCa-specific biomarkers that could identify more aggressive tumor types and therefore provide prognostic value. Upregulation of expression of human telomerase reverse transcriptase (hTERT), Survivin, DD3 and PCGEM1 mRNAs in PCa lesions has recently been described. The purpose of this study was to evaluate the clinical value of detection of over-expression of these biomarkers in the diagnosis and prognosis of PCa. MATERIAL AND METHODS: Archival formalin-fixed, paraffin-embedded (FFPE) prostatectomy tissue from 26 patients with PCa (Gleason score 3-9, mean 7) and 14 patients with benign prostatic hyperplasia (BPH) were analyzed by reverse transcription polymerase chain reaction (RT-PCR) for semiquantitative transcript levels of hTERT, Survivin, DD3 and PCGEM1. In addition, 25 matched normal (MN) tissue samples were examined. The expression of biomarker mRNA relative to b2-microglobulin mRNA was determined using AlphaImager 2200 data analysis software. RESULTS: The biomarkers had sensitivities ranging from 91% to 100%. Clinical specificities evaluated with the BPH tissue were the following: hTERT mRNA (93%), DD3 mRNA (57%), Survivin (29%) and PCGEM1 (14%). Biomarker expressions were up to 13.5-fold higher in PCa tissue as compared to MN tissue. None of the tumor biomarkers showed a positive correlation with pathological stage and Gleason score. CONCLUSIONS: The results of this study indicate potential utility of the hTERT mRNA and DD3 mRNA as diagnostic but not prognostic biomarkers for PCa.

Antigens, Neoplasm↗
PubMed1991

A single 3.7-kilobase messenger RNA hybridizes to immediate-early promoter enhancer of human cytomegalovirus in HL-60 and acute myeloid leukemia cells.

Expression of a mRNA cross-hybridized to human cytomegalovirus immediate-early gene promoter-enhancer was detected in the human promyelocytic leukemia cell line HL-60. The 0.6 kilobase of NruI/SacI DNA fragment of eukaryotic expression vector pCDM8 representing human cytomegalovirus immediate-early gene promoter-enhancer was used as the probe to hybridize with polyadenylated RNA by the Northern blot analysis. A 3.7-kilobase strand of polyadenylated RNA was visualized in the cytoplasmic fraction of HL-60 promyelocytes. In contrast, other human hematopoietic cell lines, hepatoma cells, and normal human fibroblasts did not show such a transcript by cross-hybridization. This transcript was called CMVE RNA. The expression of CMVE mRNA was also detectable in the fresh blast cells from patients with acute myeloid leukemia, and particularly from a patient with acute myeloid leukemia of the M3 type. Taken together, these findings suggest that the CMVE RNA-encoded gene plays an important role in the pathogenesis of acute promyelocytic leukemia.

Acute Disease↗
PubMed1991

Differential regulation of the stability of cyclic AMP-dependent protein kinase messenger RNA in normal versus neoplastic mouse lung epithelial cells.

Neoplastic mouse lung epithelial cells contain greatly diminished activity, protein, and mRNA for the type I isozyme of cyclic AMP-dependent protein kinase (PKA I), while expression of the type II isozyme (PKA II) is similar to that of normal lung cells. A time course of PKA mRNA content in transcriptionally inhibited cells indicated that most PKA mRNAs are more stable in the neoplastic E9 cell line than in related nontumorigenic C10 cells. To address the basis of this differential stability, we treated both cell lines with cycloheximide, an inhibitor of protein synthesis, in the presence or absence of the transcriptional inhibitor, 5,6-dichloro-1-b-ribofuranosyl-benzimidazole (DRB). The rate of PKA II regulatory subunit alpha mRNA decay in the presence of DRB was unaffected by cycloheximide treatment in E9 cells but decreased upon the addition of cycloheximide to DRB-treated C10 cells. The combination of these two agents markedly destabilized PKA II mRNAs (PKA catalytic subunit alpha and PKA II regulatory subunit alpha) relative to DRB treatment alone in neoplastic E9 cells, causing them to decay at a rate equal to that in C10 cells. PKA II mRNA may be specifically stabilized by a protein with a relatively short half-life in neoplastic E9 cells. These results suggest the involvement of tumor-specific factor(s) in the regulation of PKA mRNA stability, a potential mechanism for conferring the observed differential responsiveness of normal and neoplastic lung cells to cyclic AMP.

Animals↗
PubMed1991

Tumor necrosis factor alpha modulates the messenger RNA expression of hematopoietic growth factor genes in fresh blast cells from patients with acute myeloblastic leukemia.

Tumor necrosis factor alpha (TNF-alpha) has been previously shown to modulate the expression of hematopoietic growth factor genes in monocytes and other mesenchymal cells. As acute myeloblastic leukemia (AML) blasts can express and produce hematopoietic growth factors, the influence of TNF-alpha on the accumulation of mRNAs for c-myc, interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, IL-6 and IL-1 beta was evaluated in fresh blasts from 13 patients with AML. Total cellular RNA was extracted from blast cells cultured for 24 hours with or without TNF-alpha (500 U/ml). The c-myc transcript level was decreased by TNF-alpha treatment in 9/13 cases, and increased in only one case. Among the growth factor genes, the GM-CSF gene was more often and consistently influenced by TNF-alpha, increased levels of its transcript being observed in 6/13 cases following treatment with the cytokine; in no case was there a reduction of GM-CSF mRNA. G-CSF and IL-6 transcripts were more heterogeneously influenced, whereas the IL-3 transcript was never detected in our AML samples. The IL-1 beta message was present in 8/13 untreated and in 13/13 TNF-alpha treated samples. Moreover, in untreated cells, GM-CSF, G-CSF and IL-6 expression was always associated with IL-beta expression. These findings indicate that TNF-alpha can modulate the levels of growth factor transcripts in AML blasts, and raise questions about the effects of TNF-alpha on leukemic hematopoiesis, considering that TNF-alpha, IL-1 and GM-CSF can synergistically stimulate the growth of AML clonogenic cells.

Gene Expression Regulation, Leukemic↗
PubMedDate not supplied

Elevated c-myc messenger RNA in multiple myeloma cell lines.

Oncogene analyses of four human myeloma cell lines provided no indication of gene amplification or rearrangement using DNA probes for the met, raf, abl, mos, erb B, Her-2-neu, fos, myb-7, fms, L-myc, sis, and myb-1 genes. However, a consistent elevation of up to 23-fold in the level of c-myc mRNA was observed in all of the cell lines studied. No restriction fragment length polymorphism (in exons one, two, or three) or c-myc gene amplification has as yet been demonstrated to account for the c-myc mRNA elevation. The c-myc mRNA has a half-life of 25 min which is comparable to that observed in other systems. The elevation in c-myc mRNA is further evidence for the role of the c-myc proto-oncogene in the pathogenesis of myeloma.

DNA Probes↗
PubMed1990

Expression of a Mr 32,000 laminin-binding protein messenger RNA in human colon carcinoma correlates with disease progression.

Cell surface receptors for laminin may play an important role in tumor migration and metastasis. To evaluate laminin receptor/laminin-binding protein expression in human colon carcinoma, surgical specimens of primary colon cancers and liver metastases were examined by blot hybridization of total RNA with a complementary DNA clone which encodes a Mr 32,000 human laminin-binding protein. The mRNA level of the laminin-binding protein was higher in primary colon carcinoma than in adjacent normal colonic epithelium in 20 of 21 cases. In all 6 cases of colon cancer liver metastases, the laminin-binding protein mRNA level was more than 3-fold greater in tumor than in adjacent normal liver tissue. The tumor/normal ratio of this laminin-binding protein mRNA expression in primary colon cancer has significant correlation with Dukes' classification (P less than 0.001). Our results suggest that mRNA expression of the laminin-binding protein may be a marker of human colorectal cancer progression and biological aggressiveness.

Adenocarcinoma↗
PubMed1978

Cell-free systems for in vitro translation of herpes simplex virus messenger RNA.

A cell-free system active in translation of HSV mRNA was obtained by fractionation of reticulocyte lysates. Endogenous protein synthesis was further reduced by preincubation with micrococcal nuclease, although this treatment did not affect the translation of infected (or uninfected) BHK cell RNA. Polypeptides synthesized by the fractionated reticulocyte cell-free system were very similar to those produced by unfractionated reticulocyte lysates.

Cell Fractionation↗