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)

In a retrospective and prospective follow-up study from 1968 to 1989, bone marrow biopsy specimens, serum beta-2-microglobulin (SB2M) levels, and the clinical features of 251 patients with multiple myeloma (MM) and 28 patients with monoclonal gammopathy of undetermined significance (MGUS) were investigated. The main histologic variables (tumor cell type, tumor growth, tumor load, and fibrosis), SB2M level, serum thymidine kinase (STK) level, and various clinical parameters were analyzed to determine factors of value in monitoring the clinical phases of activity in MM. Our recently proposed prognostic strategy combining bone marrow histologic type, SB2M level, and signs of organ failure was tested for its ability to (1) diagnose the early and smoldering variants; (2) facilitate decisions on the time of initiation, the type and duration of initial induction therapy in the pretreatment phases (active and rapidly progressive phases); and (3) characterize variations in tumor regression and tumor-host interactions during chemotherapy (early treatment, plateau, relapse, transition, and refractory phases). The results indicate that this clinicopathologic monitoring combines information both on stage and aggressivity of MM and thus facilitates therapeutic decisions in the various clinical phases of MM.
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PMID:Histologic, biochemical, and clinical parameters for monitoring multiple myeloma. 191 61

The dose limitations imposed on cancer chemotherapeutic agents by their lack of selectivity can, in theory, be circumvented by a strategy entailing the prophylactic insertion into hosts of drug-sensitivity genes that are acquired or expressed in some but not all cells. This strategy predicts that neoplasms arising from drug-sensitive cells might be safely treatable with tumor-eradicative drug doses because the presence of a modicum of drug-insensitive stem cells will protect vital tissues from lethal depopulation. To test this prediction, lymphomas were induced with Abelson leukemia virus in mice bearing a herpes simplex virus thymidine kinase (HSV-TK) transgene selectively expressed in lymphoid cells. Of 12 transgenic mice treated with the HSV-TK-specific substrate ganciclovir (GCV), 11 exhibited complete tumor regressions; 5 of these mice remained tumor-free over observation periods that exceeded 100 days. Among the lymphomas that recurred, most appeared to represent mutant subpopulations that were GCV-insensitive because they had lost HSV-TK, implying that independent insertion of multiple HSV-TK gene copies might provide a means of preventing recurrences. The results of this study demonstrate that chemosensitivity genes can enhance the efficacy of treatment in hosts who subsequently develop a neoplasm. While the use of a germ-line gene insertion model precludes direct human application, the results also imply the merits of exploring an alternative version of the strategy in which somatic insertion of chemosensitivity genes in mosaic fashion is used prophylactically to enhance the prospect that a subsequent tumor will respond to therapy.
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PMID:Lymphoma regression induced by ganciclovir in mice bearing a herpes thymidine kinase transgene. 196 92

An improved method for the detection of thymidine kinase (TK) activity with the use of 125I-iododeoxyuridine as the substrate. Radioimmunoassay of prolifigen TK "Daiichi", was used for this assay. Eighty-seven serum samples were collected from 40 patients with acute nonlymphocytic leukemia in four institutions. The levels of TK were measured in the time of pretreatment, remission, and recurrence, and the relationship between the levels of TK and either LDH, marrow blasts, or circulating blasts was also examined. The levels of TK were significantly lower in the state of remission than in the pretreatment. However, the level of TK in remission was much elevated in the majority of cases than normal range (less than or equal to 5 units/l). On the contrary, LDH in remission was within normal limits in the majority of cases. The level of TK in the state of relapse was significantly higher than in the remission. The level of TK correlated in some extent with the percentage of marrow blasts (r = 0.508), and the level of TK in more than 5% of marrow blast was most beyond normal range. Correlation coefficient between the percentage of circulating blasts and TK (r = 0.577) was slightly higher than that between the percentage of marrow blasts and TK. Correlation coefficient between the level of TK and the number of marrow blasts was higher than that between LDH and number of marrow blasts. The levels of TK correlated well with serum LDH (r = 0.778), and was more sensitive than LDH. In conclusion, it was suggested that TK could be used as one of an useful and supplemental tumor marker in the follow-up of treatment of acute nonlymphocytic leukemia and to monitor the effect of therapy.
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PMID:[Clinical application of thymidine kinase activity in patients with acute non-lymphocytic leukemia]. 198 2

The aim of the present study was to characterize rat mucosal colonic cells harvested from the crypt continuum during differentiation and dimethylhydrazine-induced neoplasia. The collection of colonocytes was performed using a modified nonenzymatic isolation procedure based on Ca2+ chelation and gentle mechanical dissociation. Light and electron microscopy histomorphological examinations, [3H]thymidine incorporation studies, and activity gradients of alkaline phosphatase, thymidine kinase, and cytoskeleton-associated protein tyrosine kinase indicated that distinct cell populations were harvested from the various crypt regions in a temporal sequence mirroring their zonal and functional distribution in situ. After dimethylhydrazine administration, marked protein tyrosine kinase activity was noted in colonic cells harvested from upper crypt zones. The misplaced and sustained kinase activity preceded the actual polyp or tumor formation. This observation is consistent with the expansion of colonic proliferative compartments beyond allowable boundaries during the preneoplastic period. Companion studies in human colonic epithelial specimens corroborate the findings observed in normal and transformed murine colonocytes. It is believed that the characterization and manipulation of colonocytes using our in vitro model will provide important clues to the molecular events underlying the differentiation program and carcinogenic process in the colonic cell.
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PMID:Isolation and characterization of normal and neoplastic colonic epithelial cell populations. 199 90

The relationship between chromosome anomalies and metabolic modifications in human colorectal cancers grafted into nude mice was studied. Two distinct chromosomal patterns have been demonstrated i.e., monosomic type (MT) characterized by multiple chromosome losses or deletions always involving chromosome 18, and trisomic type (TT) characterized by progressive gains of chromosomes. Grafted tumors conserve original karyotypes observed on corresponding primary tumors. Most changes involve the loss of chromosomes carrying genes encoding for enzymes of the de novo pathways and the gain of chromosomes carrying genes encoding for enzymes of the salvage pathways of nucleotide synthesis. In MT tumors the long arm (q) of chromosome 17 is frequently duplicated in association with a deletion of the short arm, forming an isochromosome 17q. The activities of 3 enzymes, thymidylate synthetase (TS) mapped on chromosome 18, thymidine kinase (TK) and galactokinase (GalK), both mapped on chromosome 17q, were studied. TS is a de novo enzyme and TK and GalK are salvage enzymes. A clear correlation could be demonstrated between tumor types and enzyme activities: MT tumors had lower TS and higher TK and GalK activities than TT tumors. These differences were too large to result from a gene dosage effect only. These data suggest that serial studies on grafted colorectal cancers give a better representation of metabolic disturbances than studies on fresh tumor samples, usually contaminated by non-cancerous cells.
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PMID:Activity of thymidylate synthetase, thymidine kinase and galactokinase in primary and xenografted human colorectal cancers in relation to their chromosomal patterns. 200 48

The 10 isoenzyme markers discussed here represent those that in the author's judgment show promise as effective tumor markers. The relative usefulness of these isoenzymes as tumor markers is summarized in Table 6. Each isoenzyme is evaluated by a rating system, with a scale of 0-5 points in each of seven categories. The hypothetical ideal tumor marker received 5 points in all seven categories for a total score of 35. Unfortunately, less than perfect scores ranging from 9 to 26 were found for the 10 isoenzymes evaluated here. The five best isoenzymes were neuron-specific enolase (26 points), prostatic acid phosphatase (23 points), placental alkaline phosphatase (20 points), thymidine kinase 1 (16 points), and lactate dehydrogenase 1 (16 points). In general, low isoenzyme scores can be attributed to the problems exhibited by all tumor markers: insensitivity to early-stage malignancies and false-positive elevations in nonmalignant diseases. Nevertheless, each of the 10 isoenzymes described here has potential clinical usefulness to support a diagnosis of cancer and/or to assist in the monitoring of therapy.
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PMID:Serum isoenzymes in cancer diagnosis and management. 210 May 75

The transcriptionally active RVL3-VL30 element contains a triple repeat of TGACTCC, a sequence nearly identical to the AP-1 binding site. However, 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulation was unable to elicit chloramphenicol acetyltransferase (CAT) expression from a construct containing these AP-1-like sequences upstream of the thymidine kinase promoter present in pTES. Endothelin, which activates protein kinase C (pkC) and elevates intracellular Ca2+ in Rat-1 cells, was effective in stimulating CAT expression from the VL30-pTES construct. We attempted to assess the relative importance of these second messenger systems by stimulating each pathway separately with exogenous agonists. We determined that neither stimulation of pkC by the tumor promoter TPA nor elevation of intracellular Ca2+ by the tumor promoter thapsigargin was sufficient to stimulate CAT expression from the VL30-pTES vector. When combined, the two tumor promoters induced a synergistic increase in CAT expression. Our data indicate that elevation of intracellular Ca2+ by thapsigargin was not required for full activation of pkC by TPA. First, TPA was able to stimulate expression of other genes in Rat-1 cells, indicating full activation of pkC. Second, thapsigargin synergized effectively with epidermal growth factor to stimulate CAT activity from the VL30-pTES construct in cells depleted of pkC activity by chronic TPA treatment. The permissive effects of thapsigargin on gene expression were also observed for an endogenous gene, transin/stromelysin. The permissive effects of elevated intracellular Ca2+ levels may represent a general mechanism for the stimulation of some genes by pkC-mediated pathways.
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PMID:Two tumor promoters, 12-O-tetradecanoylphorbol-13-acetate and thapsigargin, act synergistically via distinct signaling pathways to stimulate gene expression. 212 50

Age-related changes in the activity of thymidine- and adenosine-metabolizing enzymes were studied in healthy females and those with breast cancer aged 46-70 years. A significant increase in activity of thymidine kinase, adenosine deaminase and 5'-nucleotidase and a decrease in that of thymidine phosphorylase were registered in blood serum of breast cancer patients of all age brackets. Adenosine deaminase activity in blood serum and lymphocytes of breast cancer patients was found to significantly change after surgery. A direct correlation was established between pretreatment thymidine phosphorylase activity and histological type of tumor, on the one hand and results of chemotherapy, on the other. The applicability of enzyme level assay for evaluating response to pre- and postoperative medication was studied.
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PMID:[Activity of the enzymes of DNA metabolism in the blood of patients with breast cancer]. 215 96

The interferon (IFN)-gamma-mediated induction of indoleamine 2,3-dioxygenase (IDO) enzyme, which converts tryptophan into N-formylkynurenine, has been implicated in the inhibition of intracellular pathogens, e.g. Toxoplasma gondii and Chlamydia psittaci, and in the antiproliferative effect of IFN-gamma on tumor cells. The IDO activity is induced strongly in many cell types by IFN-gamma but rather poorly by IFN-alpha or -beta. A genomic DNA clone containing part of the transcribed region of the IDO gene and approximately 13 kilobases (kb) of the 5'-upstream DNA sequence was isolated and analyzed. An approximately 1.4-kb fragment of this clone, containing 329 nucleotides of the transcribed sequence and approximately 1.1 kb of the 5'-upstream sequence, when ligated to chloramphenicol acetyltransferase (CAT) structural gene made its expression inducible by IFN-gamma, but this construct responded poorly, if at all, to IFN-alpha 2. Deletion constructs derived from this plasmid narrowed down the IFN-gamma-responsive region to a 151-nucleotide segment (-495/-344) which also contained a 14-nucleotide sequence (GGTTTCAGTTTTCC) highly homologous to the IFN(alpha)-stimulated response element (ISRE) that has been found so far in all cellular genes inducible with IFN-alpha or -beta. Expression of CAT activity was stimulated by IFN-gamma more effectively than by IFN-alpha 2 when a 155-nucleotide fragment (-495/-340) containing the 151-nucleotide segment required for IFN-gamma response was inserted before herpes simplex virus thymidine kinase promoter linked to CAT structural gene. The results indicate that despite the presence of an ISRE, the control region of the IDO gene can distinguish between IFN-gamma and IFN-alpha. This may account for the differential activation of IDO gene expression by IFN-gamma as against IFN-alpha or -beta in intact cells, and suggests that the response of ISRE to IFN-alpha or -beta may be governed by other features in the upstream control region of this gene.
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PMID:Regulation of indoleamine 2,3-dioxygenase gene expression in human fibroblasts by interferon-gamma. Upstream control region discriminates between interferon-gamma and interferon-alpha. 217 56

Proteolysis by type IV collagenase (T4) has been implicated in the process of tumor metastasis. The T4 gene is expressed in fibroblasts, but not in normal epithelial cells, and its expression is specifically repressed by the E1A oncogene of adenovirus. We present an investigation of the transcriptional elements responsible for basal, E1A-repressible, and tissue-specific expression. 5'-Deletion analysis, DNase I footprinting, and gel mobility shift assays revealed a strong, E1A-repressible enhancer element, r2, located about 1,650 bp upstream of the start site. This enhancer bound a protein with binding specificity very similar to that of the transcription factor AP-2. A potent silencer sequence was found 2 to 5 bp downstream of this enhancer. The silencer repressed transcription from either r2 or AP-1 enhancer elements and in the context of either type IV collagenase or thymidine kinase (tk) gene core promoters; enhancerless transcription from the latter core promoter was also repressed. Comprising the silencer were two contiguous, autonomously functioning silencer elements. Negative regulation of T4 transcription by at least two factors was demonstrated. mcf-7 proteins specifically binding both elements were detected by gel mobility shift assays; a protein of approximately 185 kDa that bound to one of these elements was detected by DNA-protein cross-linking. The silencer repressed transcription, in an r2 enhancer-tk promoter context, much more efficiently in T4-nonproducing cells (mcf-7 or HeLa) than in T4-producing cells (HT1080), suggesting that cell type-specific silencing may contribute to the regulation of this gene.
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PMID:Positive and negative transcriptional elements of the human type IV collagenase gene. 217 9


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