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)

Specific biochemical molecules used as potential biologic markers, including modified nucleosides, polyamines, and pyrimidine catabolic end-products, were quantitatively measured in the urine of seven patients with Burkitt's lymphoma before, during, and after one or more courses of therapy. The results of this preliminary study demonstrated that patients with this disease frequently excrete significantly increased amounts oof modified nuceleosides (considered to be derived primarily from transfer ribonucleic acid), polyamines, and beta-aminoisobutyric acid during the course of their disease. With successful treatment and rapid destruction of tumor cells, a concomitant rise in these molecules occurs. Elevations were observed prior to chemotherapy and changes in levels associated with treatment or tumor progression appeared to correlate with disease status and to aid in assessing antitumor response. Periodic follow-up analysis of these molecules may be helfful in appraising relapse or recurrence of the malignancy prior to overt evidence of tumor by existing clincial means.
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PMID:Potential biologic markers in Burkitt's lymphoma. 117 66

The studies described indicate that me-t-IMP formation is an important pathway, contributing to cytotoxicity in Molt F4 cells, which exhibit a highly active de novo purine synthesis. On three levels cytotoxicity is induced during methylation of thiopurines. 1. Purine synthesis de novo is inhibited during formation of me-t-IMP. Inhibition of PDNS results in depletion of purine nucleotides, with subsequently diminishing DNA and RNA synthesis. 2. The increased PRPP levels, induced by me-T-IMP, induce increased pyrimidine biosynthesis and cause an imbalance in purine nucleotides. This imbalance may lead to inhibition of cell growth and after prolonged exposure, to cell death. 3. The observed depletion of SAM and the decrease of the SAM/SAH ratio may be an additional mechanism by which 6MP and me-MPR exert their effects on cell growth and cell viability. Changes in SAM/SAH ratio may directly influence methylation reactions. The significant decrease of DNA methylation by 6MP and me-t-IMP may influence gene regulation and tumor progression. Administration of SAM leads to chemoprevention of rat liver carcinogenesis, indicating a role of DNA methylation in tumor progression. Besides the effects on methylation of DNA, a decrease of SAM/SAH ratio may also affect other processes, such as methylation of RNA, proteins and phospholipids, thereby disturbing their functionality. In conclusion, decrease of the SAM/SAH ratio resulting from treatment with 6MP and me-MPR may exert many effects in these cells. This may open a new field of research, possibly contributing to a deeper understanding of the complex mechanisms by which 6MP provokes cytotoxicity.
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PMID:Thiopurine induced disturbance of DNA methylation in human malignant cells. 757 47

N- and K-ras oncogene mutations represent the most frequent molecular lesions in plasma cell dyscrasias. They are not randomly distributed since they are detectable in multiple myeloma (MM) (9-31%) and plasma cell leukemia (PCL) (30%), and not in monoclonal gammopathy of undetermined significance (MGUS) and solitary plasmacytoma (SP). Codons 12, 13 and 61 of N- and K-ras genes have been found mutated. Mutations affecting codon 61 of N-ras gene are the most frequent finding. A heterogeneous pattern of mutations is described with a prevalence of purine-pyrimidine transversions. Ras gene mutations have been predominantly detected in myelomas characterized by an advanced stage disease, and adverse prognostic parameters. These findings suggest that ras mutations represent a late molecular lesion and may be implicated in tumor progression rather than tumor initiation.
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PMID:N- and K-ras oncogenes in plasma cell dyscrasias. 785 96

We have investigated the genetic stability of NIH-3T3 cells transfected with sequences coding for basic fibroblast growth factor (bFGF) by determining drug resistance and gene amplification potential. Colony-forming experiments and fluctuation analyses showed that the frequency and rate of resistance to N-(phosphonacetyl)-L-aspartate (PALA) was dramatically elevated in cells transfected with either the normal bFGF coding sequence that lacks a known signal for secretion or a chimeric bFGF sequence that targets the growth factor to the secretory pathway. Basic FGF-transfected cells that grew in the presence of PALA were found to possess an amplification of the CAD gene, which codes for a multifunctional protein involved in pyrimidine biosynthesis and is the site of action for PALA. The observation that these alterations occur in cells transfected with a bFGF sequence, without a conventional signal sequence for secretion, suggests an intracrine as opposed to autocrine mechanism of action. The results describe a new function for this growth factor and suggest a novel role for aberrant expression of bFGF in mechanisms of tumor progression.
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PMID:Aberrant expression of basic fibroblast growth factor in NIH-3T3 cells alters drug resistance and gene amplification potential. 805 Apr 90

In order to study the role of DNA damage processing in the development of cutaneous squamous cell carcinoma (SCC), we assessed the ability of six keratinocyte cell lines from a multistage-tumor progression model to repair three types of DNA damage: pyrimidine dimers, oxidative DNA lesions and DNA double strand breaks (DSB). The model comprised the spontaneously immortalized, non-tumorigenic human keratinocyte cell line HaCaT, four different c-Ha-ras transfectants of HaCaT (non-, benign- and two malignant-tumorigenic) and a SCC-derived cell line. Host cell reactivation assays with UVB-treated plasmid vectors pRSVcat showed no significantly altered repair of UVB-induced pyrimidine dimers in the tumorigenic cell lines, compared with the non-tumorigenic lines. Using the singlet oxygen-treated plasmids pRSVcat the Ha-ras-HaCaT-clones and the SCC-cells, exerted a DNA repair efficiency that was not significantly different from HaCaT cells. In order to assess the ability of the cells to ligate free DNA ends (repair of DSB), we used a plasmid shuttle vector assay with linearized plasmid pZ189. We found a significant increase of DNA end joining ability in the non-tumorigenic, the benign and in one of the malignant HaCaT-clones II-4. The malignant HaCaT-clone II-3, however, exerted a significantly lower rate of rejoining the linearized plasmid. This cell line also showed a highly and significantly elevated rate of micronuclei, which reflects a pronounced chromosomal instability. The SCC-cells exhibited a more efficient repair of DNA DSB than the HaCaT cells. We conclude that in the examined model, progression of human keratinocytes from the non-tumorigenic to the highly tumorigenic phenotype, is not accompanied by a decrease in the cell's capacity to repair UVB- and singlet oxygen-induced DNA lesions. However, an acquired deficiency in repairing DNA double strand breaks can be one mechanism promoting progression towards malignancy, possibly through impairing chromosomal stability.
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PMID:Processing of three different types of DNA damage in cell lines of a cutaneous squamous cell carcinoma progression model. 911 Nov 96

The use of antisense oligonucleotides in cell culture relies on the development of potent modifications and cell delivery techniques. C-5 propyne pyrimidine phosphorothioate oligonucleotides bind selectively and with high affinity to RNA within cells, leading to potent antisense inhibition. The effect that increasing steric bulk of C-5-substituted deoxyuridine analogues has on the affinity for RNA and the ability to inhibit gene expression is discussed. The GS 2888 cytofectin agent delivers oligonucleotides to cells at high efficiency in the presence of serum in cell media. Modifications leading to the discovery of GS 2888 centered on the aliphatic chain length of the molecule and the pKa of the polar head group. Together, the C-5 propyne modifications and the GS 2888 cytofectin agent have been shown to be effective inhibitors of gene expression in cell culture, particularly in the area of cell cycle proteins involved in cancer progression.
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PMID:Structure-activity relationships in cell culture. 938 74

In this report we present evidence for a novel switch in the ratio of the two major isoforms of the polypyrimidine tract binding protein (PTB) in two related prostate cancer cell lines. The existence of different isoforms of PTB is thought to be the result of alternative splicing. We used UV cross-linking to identify a PTB doublet in the DT3 cell line, which is a rat prostate epithelial cancer line that is androgen-dependent and nonmetastatic. The AT3 cell line, a metastatic, androgen-independent cell line derived from the same tumor as the DT3 cells, was noted here to have a different isoform ratio of PTB. The two most prevalent isoforms of PTB were found to bind to an RNA probe containing a pyrimidine stretch. Western blot analysis demonstrated that these isoforms are indeed expressed differently in the two cell lines and that the observed binding is the result of this differential expression. These two cell lines are derived from the original Dunning prostate tumor, which is a model for studying tumor progression in the prostate. This ratio switch may be an important event in tumor progression in this model system of prostate cancer.
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PMID:A novel isoform ratio switch of the polypyrimidine tract binding protein. 1034 88

We have demonstrated previously that the GT triplex-forming oligodeoxyribonucleotide (TFO) d(TGTGTTTTTGTTTTGTTGGTTTTGTTT), named TFO ID, targeted to a polypyrimidine-polypurine coding sequence located within human multidrug-resistance mdrl gene, specifically and significantly reduced mdrl mRNA levels in the drug-resistant T-leukemic CEM-VLB100 cell line. In this article, we demonstrate that TFO 1D is effective at inhibiting not only transcription but also replication of mdrl genes, leading to a loss of amplified gene copies in the drug-resistant colon adenocarcinoma LoVo DX cell line. In contrast, TFO ID does not alter replication of the constitutive mdrl gene copy in the corresponding parental sensitive LoVo 109 cell line. A specific reduction in mdrl gene amplification levels was also obtained with the pyrimidine TFO d(CTTTTTCTTTTCTTCCTTTTCTTT), named TFO 24TC, directed against the same polypyrimidine-polypurine sequence of the mdrl gene. We suggest that triple helix-forming oligonucleotides might affect the replication of unstable chromosomal elements as amplicons in actively replicating cells by causing a local impairment of DNA polymerase activity. This study lends support to the notion that TFO may be used to reduce gene amplification aiming to control neoplastic progression in cancer cells bearing amplified oncogenes.
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PMID:Reduction of mdr1 gene amplification in human multidrug-resistant LoVo DX cell line is promoted by triple helix-forming oligonucleotides. 1043 51

The melanoma cell adhesion molecule is a membrane glycoprotein whose expression is associated with tumor progression and the development of metastatic potential. The mechanisms for upregulation of the melanoma cell adhesion molecule during melanoma progression are still poorly understood. In this study, we show further evidence that melanoma cell adhesion molecule expression is tightly regulated at the transcriptional level. Using a combination of chloramphenicol acetyl transferase reporter assays and DNA mobility shift experiments, we investigated the role played by three putative melanoma cell adhesion molecule regulatory elements, namely the initiator sequence, the SCA element, and the ASp element. The SCA and the ASp boxes can potentially interact with the transcription factors Sp1 and AP-2. Sp1 binding to both sites was confirmed, but only the SCA sequence could form a complex with AP-2. AP-2-driven downregulation of the melanoma cell adhesion molecule promoter, however, did not depend only on a functional SCA element. The pyrimidine-rich CTCACTTG initiator, which overlaps the RNA start site, was essential for promoter function and was shown to interact with proteins related to basic helix-loop-helix transcription factors. Binding in nonmetastatic melanoma cells was induced by cAMP. In metastatic cells, however, binding was constitutive, but could be markedly decreased upon treatment with phorbol esters. As melanoma cell adhesion molecule expression is modulated by cAMP and phorbol ester signaling, these results suggest that the initiator is the central element that mediates cAMP and phorbol ester sensitivity and initiates melanoma cell adhesion molecule overexpression in melanomas.
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PMID:Role of the initiator element in the regulation of the melanoma cell adhesion molecule gene. 1099 41

Thymidylate synthase (TS) is a crucial target for 5-fluorouracil (5-FU) in the de novo pathway of pyrimidine synthesis, which is necessary for DNA synthesis. Thymidine kinase (TK) plays a key role in the complementary or alternative salvage pathway of pyrimidine synthesis in acute or pathological tissue stress. In the present study, the activity levels of TS and TK were determined in 257 primary breast tumors of patients who received tamoxifen as first-line systemic therapy after diagnosis of advanced disease. In 155 (60%) responding patients, the median response duration was 23 months for tumors with low TK activity, 15 months for tumors with intermediate TK activity, and 13 months for tumors with high TK activity (P = 0.003). In Cox multivariate analysis corrected for classical predictive factors including estrogen receptor and progesterone receptor, patients with intermediate and high levels of TK activity in their tumors showed a rapid disease progression (P = 0.0002) and an early death (P = 0.002) after start of tamoxifen treatment. Tumor TS activity levels were not significantly associated with the efficacy of tamoxifen treatment. In 121 patients who became resistant to tamoxifen or additional endocrine treatments and who received 5-FU-containing polychemotherapy, tumor TK activity was not significantly related to the efficacy of chemotherapy. Of the 13 patients with low tumor TS activity, only 1 (8%) responded favorably, whereas 46% (43 of 93) of those with intermediate and 73% (11 of 15) of those with high TS activity responded (P = 0.001). In Cox multivariate regression analysis in which TS was the only significant variable, intermediate and high TS activities were associated with a slow disease progression (P = 0.005) and prolonged survival (P = 0.016) on chemotherapy. In conclusion, for patients with recurrent breast cancer, high tumor TK activity is a significant marker of poor clinical outcome on tamoxifen therapy. Elevated tumor TS activity predicts a favorable outcome for 5-FU-containing polychemotherapy when applied after tumor progression on endocrine therapy.
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PMID:Thymidine kinase and thymidylate synthase in advanced breast cancer: response to tamoxifen and chemotherapy. 1124 45


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