UMLS:C0677930 - FACTA Search

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Query: UMLS:C0677930 (primary tumor)
20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

O6-Alkylguanines, important DNA adducts formed by alkylating agents, can lead to mutations and to cell death unless repaired. The major pathway of repair involves the transfer of the alkyl group from the DNA to a cysteine acceptor site in the protein O6-alkylguanine-DNA alkyltransferase. The alkyltransferase brings about this transfer without need for cofactors and the DNA is restored completely by the action of a single protein, but the cysteine acceptor site is not regenerated and the number of O6-alkylguanines that can be repaired is equal to the number of active alkyltransferase molecules. The alkylated form of the protein is unstable in mammalian cells and is degraded rapidly. Cloning of the cDNAs for the alkyltransferase proteins from bacteria, yeast, and mammals indicates a significant similarity, particularly in the region surrounding the cysteine acceptor site. There is a major difference in the regulation of the alkyltransferase between mammalian cells and certain bacteria, where it is induced as part of the adaptive response to alkylating agents. Regulation of the content of alkyltransferase in mammalian cells differs with species and cell type and, in some cases, the level of the protein is increased by exposure to alkylating agents or X rays. A significant fraction of human tumor cell lines do not express the alkyltransferase gene and, thus, are much more sensitive to mutagenesis and killing by alkylating agents. The frequency of primary tumor cells that lack alkyltransferase protein is not yet clear. However, it is known that the level of alkyltransferase in tumors is a significant factor in resistance to both methylating agents and bifunctional chloroethylating agents. Inactivation of the alkyltransferase, which can be brought about by pretreatment with an alkylating agent or by exposure to O6-benzylguanine (a powerful nontoxic inhibitor), sensitizes tumor cells to these chemotherapeutic alkylating agents and may prove a useful therapeutic strategy.
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PMID:Repair of DNA containing O6-alkylguanine. 154 41

Methionine-depleting total parenteral nutrition (methionine-depleting TPN), which infuses an amino acid solution devoid of L-methionine and L-cysteine as the sole protein source, showed enhancement of the effect of several anti-cancer agents. In this study, the combined effect of the methionine-depleting TPN with the administration of doxorubicin was examined in Yoshida sarcoma (YS)-bearing rats with regard to effects on the primary tumor growth, the extension of metastasis, and the host animal's life span. In the first experiment, immediately after receiving methionine-depleting TPN for 8 days, the animals were killed. Pathologic findings evaluated tumor growth in the implanted site and extension of the metastasis. In the second experiment, the survival period was determined after animals received methionine-depleting TPN for 10 days, with subsequent oral feeding until they died naturally. Proliferation of YS was markedly suppressed. In particular, hematogenous metastasis, which is a characteristic of YS, was suppressed, and a longer survival period (42.7 +/- 15.6 days, mean +/- SD) was attained in rats in the group treated with the methionine-depleting TPN combined with the administration of doxorubicin.
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PMID:Antitumor effect of methionine-depleting total parenteral nutrition with doxorubicin administration on Yoshida sarcoma-bearing rats. 155 Oct 70

L-methionine-deprived total parenteral nutrition (methionine-deprived TPN), infusing amino acid solution devoid of L-methionine and L-cysteine by the method of TPN as an only protein source, showed enhancement of the effect of several anti-cancer agents. In this study the combined effect of the methionine-deprived TPN with administration of 5-fluorouracil (5-FU) was examined in Yoshida Sarcoma (YS)-bearing rats, from aspects of effects on the tumor metastasis and the host animal's life span, in the following four groups treated with: methionine-deprived TPN with administration of 5-FU, methionine-deprived TPN without administration of 5-FU, L-methionine-contained TPN plus 5-FU, and L-methionine-contained TPN without 5-FU. In the first experiment, TPN was continued for 8 days in the four groups, and the anti-cancer effect of methionine-deprived TPN and administration of 5-FU based on both the growth of the primary tumor at the implanted site and the tumor metastasis was studied from the view point of pathologic findings of animals killed immediately after these treatments. In experiment 2 the survival period was examined after these treatments for 10 days with subsequent oral feeding until death. The results were as follows: proliferation of YS, transplanted subcutaneously, was markedly suppressed; particularly hematogenous metastasis, characteristic in YS, was prominently blunted then obtained an apparent longer survival period in rats treated with the methionine-deprived TPN with administration of 5-FU.
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PMID:Anti-tumor effect of L-methionine-deprived total parenteral nutrition with 5-fluorouracil administration on Yoshida sarcoma-bearing rats. 190 13

We studied the effects on platelet function of cells isolated from freshly dissociated human tumor tissues (11 breast carcinomas, 9 colon carcinomas and 1 lymph node metastasis from melanoma) obtained at surgery as compared with cultured human tumor cells: namely, human melanoma 1402 cell line derived from a primary tumor and two lines derived from lymph node metastases (ME 7110/2 and Me 665/1) as well as a human hepatoma cell line (Hep G2). The three melanoma cell lines activated platelets by producing ADP, as evidenced by the inhibitory effect of apyrase and by the direct measurement of the agonist in the supernatants of tumor cell suspensions; this production was much greater by the cells derived from metastases than by the cells derived from the primary tumor. On the other hand, aggregation induced by Hep G2 hepatoma cells was unaffected by apyrase and was inhibited by hirudin or concanavalin A, suggesting that the cells aggregate platelets by producing thrombin, probably through tissue factor activity of the cells themselves. Cells isolated from 16 of the 21 human tumor tissues possessed a potent platelet-aggregating effect, which was not inhibited by apyrase, hirudin or concanavalin A, but was virtually abolished by the cysteine protease inhibitors iodoacetic acid or p-hydroxymercuri-phenylsulfonate. Collectively, our data demonstrate that cells isolated from freshly dissociated tumor tissues activate platelets through tumor-associated cysteine proteinases rather than by the ADP- or thrombin-dependent mechanisms characteristic of cultured human tumor cell lines.
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PMID:Mechanisms of platelet activation by cultured human cancer cells and cells freshly isolated from tumor tissues. 276 27

Lung cancer is the leading cause of malignancy-related mortality in the U.S. and is predicted to increase over the remainder of this decade. Despite attempts to advance early diagnosis and use combination therapies, the clinical response of this cancer yields an overall 5-year survival rate of less than 15%. Clearly, new strategies for therapy are indicated. Although carcinogenesis is complex, tumor growth beyond 1-2 mm3 is dependent on angiogenesis. One of the potential mechanisms that allows for tumorigenesis is dysregulation of the balance of angiogenic and angiostatic factors that favors net neovascularization within the primary tumor. Numerous studies have investigated the role of a variety of molecules in the regulation of angiogenesis. Recently, interleukin-8 (IL-8), a member of the C-X-C chemokine family, has been found to be an angiogenic factor. In contrast, platelet factor 4 (PF4), another C-X-C chemokine, has been shown to have angiostatic properties. It is interesting that the major structural difference between IL-8 and PF4 is the presence of the NH2-terminal ELR (Glu-Leu-Arg) motif that precedes the first cysteine amino acid residue of IL-8 and is important in ligand/receptor interactions. We hypothesize that angiogenesis associated with tumorigenesis is dependent on members of the C-X-C chemokine family acting as either angiogenic or angiostatic factors. This paradigm predicts that the biological balance in the expression of these C-X-C chemokines dictates whether the neoplasm grows and develops metastatic potential or regresses. In this review we discuss our recent laboratory findings that support this contention and suggest that further elucidation of the biology of C-X-C chemokines in the context of neovascularization of nonsmall cell lung cancer will permit novel targeted therapy aimed specifically at attenuating tumor growth and metastasis.
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PMID:Role of C-X-C chemokines as regulators of angiogenesis in lung cancer. 753 29

The thiol N-acetylcysteine (NAC) is currently considered one of the most promising cancer chemopreventive agents by virtue of its multiple and coordinated mechanisms affecting the process of chemical carcinogenesis. Recent studies have shown that an unpaired cysteine residue in the propeptide plays a key role in inactivation of latent metastasis-associated metalloproteinases: the present study was designed to assess whether NAC could also affect tumor take, invasion and metastasis of malignant cells. As assessed by zymographic analysis, NAC completely inhibited the gelatinolytic activity of type-IV collagenases in the cells tested (gelatinases A and B). Moreover, NAC was efficient in inhibiting the chemotactic and invasive activities of tumor cells of human (A2058 melanoma) and murine origin (K1735 and B16-F10 melanoma cells as well as C87 Lewis lung carcinoma cells) in Boyden-chamber assays, which are predictive of the invasive and metastatic properties. Reduced glutathione (GSH) had a similar, although less effective activity. The number of lung metastases decreased sharply when B16-F10 murine melanoma cells, injected i.v. into nude mice, were pre-treated with NAC and resuspended in medium supplemented with 10 mM NAC. In other experiments NAC was given in drinking water, starting 48-72 hr before subcutaneous inoculation of either B16-F10 cells or of their highly metastatic variant B16-BL6, or intramuscular injection of LLC cells. In all experiments NAC treatment decreased the weight of the locally formed primary tumor and produced a dose-related delay in tumor formation. Spontaneous metastasis formation by B16-F10 and B16-BL6 tumors was slightly yet significantly reduced by oral administration of NAC. However, this was not observed for Lewis lung tumors. These data indicate that NAC affects the process of tumor-cell invasion and metastasis, probably due to inhibition of gelatinases by its sulfhydryl group, with the possible contribution of other mechanisms, including the potent antioxidant activity of this thiol.
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PMID:Inhibition of invasion, gelatinase activity, tumor take and metastasis of malignant cells by N-acetylcysteine. 770 24

To study the molecular mechanisms underlying the intensive expression of acetylcholinesterase (AChE) in different tumor types, we characterized levels and composition of its messenger RNA (mRNA) sequences in heterologous tumor cell lines, primary tumor biopsies, and normal fetal and adult tissues and determined their exon-intron origin within the corresponding ACHE gene. Reverse transcription followed by polymerase chain reaction (RT-PCR) revealed three alternatively spliced ACHE mRNAs in NT2/D1 teratocarcinoma, NCI-N-592 small cell lung carcinoma, TE671 medulloblastoma, K-562 erythroleukemia, and 293 transformed embryonal kidney cells. The three ACHE mRNAs include the principal species expressed in brain and muscle and two additional transcripts containing insertions of 751 or 829 residues downstream from the exon 4 domain. The inserted region, which represents an intron in brain and muscle, is expressed in the tumor cell lines either as a "readthrough" form or with 78 residues deleted from its 5' end. A major band of 2.5 kb was labeled with ACHE cDNA in poly(A)+ RNA blots from medulloblastoma cells or brain tissue, whereas a PCR-amplified probe from the inserted domain labeled a 3.4-kb band but not the 2.5-kb band in poly(A)+ RNA from small cell lung carcinoma. The ACHE mRNAs including the alternative insertions were found only in cell lines with levels of the principal ACHE mRNA species equal to or higher than those in brain (1-10 molecules/cell), determined by following the kinetics of mRNA PCR amplification. Genomic DNA sequencing revealed that the inserted domains in the ACHE mRNAs expressed in the tumor cell lines encode C-terminal peptides of 40 and 14 residues. These include a free cysteine, terminate with the consensus HG element, and continue by a 29-residue-long C-terminal hydrophobic cleavable peptide, properties characteristic of precursors to phosphoinositide (PI)-linked proteins. In extension of the reported expression of PI-linked AChE in hemopoietic cells including K-562, our findings demonstrate the existence of ACHE mRNAs with the potential to encode one hydrophilic and two PI-linked forms of AChE in tumor cells from both hemopoietic and nonhemopoietic origins.
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PMID:Expression of three alternative acetylcholinesterase messenger RNAs in human tumor cell lines of different tissue origins. 829 25

Previous studies have identified and characterized both murine in vivo and human in vitro T cell responses reflecting specific mutations in the ras proto-oncogenes at codon 12, 13, or 61. In an attempt to determine whether peptide epitopes reflecting point mutations in the ras oncogenes are immunogenic in humans for the production of CD4+ and/or CD8+ T cell responses, a phase I clinical trial was initiated in metastatic carcinoma patients whose primary tumors harbor mutations in the K-ras proto-oncogenes at codon 12. The peptides used here as immunogens, which were administered in Detox adjuvant, spanned the ras sequence 5-17 and reflected the amino acid substitution of glycine (Gly) at position 12 to aspartic acid (Asp), cysteine (Cys), or valine (Val). Three of eight evaluable patients have demonstrated peptide-specific cell-mediated immunity, as determined by the production of T cell lines resulting from the vaccination. First, an antigen (Ag)-specific, major histocompatibility complex (MHC) class II (DP)-restricted CD4+ T cell line was established in vitro from postvaccination lymphocytes of a non-small cell lung carcinoma patient whose primary tumor contained a Cys12 mutation when cultured on the immunizing peptide. Moreover, CD4+ proliferation was inducible against the corresponding mutant K-ras protein, suggesting productive T cell receptor recognition of exogenously processed Ag. Second, an Ag-specific, MHC class I (HLA-A2)-restricted CD8+ cytotoxic T lymphocyte (CTL) line was established in vitro from postvaccination lymphocytes of a colon carcinoma patient whose primary tumor contained an Asp12 mutation. To that end, a 10-mer peptide, nested within the 13-mer immunizing peptide, was identified [i.e., ras5-14(Asp12)], which was shown to bind to HLA-A2 and display specific functional capacity for expansion of the in vivo primed CD8+ CTL precursors. Third, both Ag-specific, MHC class II (DQ)-restricted CD4+ and MHC class I-restricted (HLA-A2) CD8+ T cell lines were generated from a single patient with duodenal carcinoma whose primary tumor contained a Val12 mutation when cultured on the immunizing 13-mer peptide or a nested 10-mer peptide [i.e., ras5-14(Val12)], respectively. Evidence is thus provided that vaccination with mutant ras oncogene peptides in adjuvant may induce specific anti-ras cellular immune responses, with no detectable cross-reactivity toward normal proto-ras sequences. Moreover, we have identified for the first time human HLA-A2-restricted, CD8+ CTL epitopes reflecting specific point mutations in the K-ras oncogenes at codon 12 which, in concert with the activation of the CD4+ T cell response, may have important implications for both active and passive immunotherapies in selected cancer patients.
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PMID:Generation of stable CD4+ and CD8+ T cell lines from patients immunized with ras oncogene-derived peptides reflecting codon 12 mutations. 951 98

Lysosomal cysteine proteinases, also known as cysteine cathepsins (Cats), belong to the papain family of proteinases, and share a similar protein structure and mechanism of action. However, subtle structural differences between these cathepsins, e.g. Cats B, H and L, give rise to potentially important variations in substrate specificity and differences in inhibition by their endogenous inhibitors, the cystatins, stefins and kininogens, under physiological and pathological conditions. Alterations in expression of Cat B and Cat L have been observed at various levels in malignant human tumor tissue compared to normal and benign tissue counterparts. We proposed that an imbalance between cathepsins and cystatins, associated with the metastatic tumor cell phenotype, may facilitate tumor cell invasion and metastasis and be responsible for early relapse of the disease after removal of the primary tumor. The results of our initial investigations on cysteine cathepsins and their endogenous inhibitors in human breast, lung and head and neck carcinomas, as well as in body fluids of melanoma and colorectal carcinoma bearing patients, have indeed shown their high prognostic impact for the survival of these patients.
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PMID:Cysteine proteinases in cancer progression and their clinical relevance for prognosis. 952 63

Germline mutations of the gene encoding human fibroblast growth factor receptor 3 (FGFR3) have been shown to be responsible for several related autosomal dominant forms of syndromic craniosynostosis and short limb dwarfism. Somatic activating mutations of FGFR3 were recently reported to occur in three of 12 (25%) uterine cervical carcinomas and nine of 26 (35%) bladder carcinomas, suggesting that constitutive activation of FGFR3 may be an important mechanism underlying the development and/or progression of these common epithelial malignancies. In order to investigate further a possible role for FGFR3 mutations in cervical carcinogenesis, we performed sequence-based mutational analysis of FGFR3 in 51 primary cervical carcinomas and seven cervical carcinoma-derived cell lines. The regions analysed (exons 7, 10, 13, 15, and 19) encompassed all previously described FGFR3 mutations. A single nucleotide substitution at codon 249, predicting a serine to cysteine amino acid substitution (S249C) in the FGFR3 extracellular domain, was identified in one primary tumor. Only wild type FGFR3 alleles were identified in the remaining tumors and cell lines. The S249C mutation is the only FGFR3 mutation described to date in cervical carcinomas. These findings suggest that while activating mutations of FGFR3 occur in cervical cancer, they may not be as common as initially reported.
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PMID:Somatic mutations of fibroblast growth factor receptor 3 (FGFR3) are uncommon in carcinomas of the uterine cervix. 1111 33

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