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)

The mechanism for 5-fluorouracil (5-FU) and cisplatin (CDDP) synergism was investigated in experimental tumor models in rodents in vivo. The reduced folates such as 5, 10-methylenetetrahydrofolate (CH2FH4) and tetrahydrofolate (FH4) which play a significant role in the metabolism of 5-FU were increased about 2 to 3 fold 5 in P388 and Yoshida sarcoma cells of rodents at 24 hours following intraperitoneal administration of CDDP (5 mg/kg), and tritiated 2'-deoxyuridine incorporation into DNA fraction of the CDDP-treated cells was more strongly inhibited than that of non-treated cells after incubation with 5-FU, which indicated the increased formation of a tight ternary complex between thymidylate synthase, FdUMP derived from 5-FU and elevated CH2FH4. The combination of single intraperitoneal CDDP and 6 day-continuous infusion of 5-FU and/or 7 consecutive oral administration 5-FU derivative, BOF-A2, enhanced synergistically the antitumor activity against solid Yoshida sarcomas in rats as compared to each drug alone. These data suggest that CDDP play an important role as not only an effector but also a modulator in biochemical modulation of 5-FU in cellular methionine metabolism and by resultant elevation of intracellular reduced folates.
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PMID:[Mechanism for synergistic antitumor effect in the combination of 5-fluorouracil with cisplatin in vivo tumor models: from the view of biochemical modulation of 5-fluorouracil]. 200 40

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

MOPC-104E plasmacytomas were subcutaneously transplanted into BALB/c mice and after 7 days the mice were administered different fluorinated pyrimidines at 4 times the clinical doses, 5-fluorouracil (5-FU, 15 mg/kg), tegafur (FT, 100 mg/kg) or UFT (FT, 20 mg/kg + uracil, 44.8 mg/kg) daily for 7 days. Tumor growth was most effectively inhibited in the UFT group. The % inhibition of tumor growth on day 14, while not correlating with the concentration of 5-FU in the tumor, negatively correlated with the concentration of uracil, which was lowest in the UFT group. The activity of thymidylate synthase (TS) was measured using a 5-fluoro-deoxyuridine monophosphate (FdUMP) binding assay. The total and free TS activities in the tumor negatively correlated with the % inhibition of tumor growth, and were lowest in the UFT group. However, the % inhibition of TS activity in the tumor, which was about 80% in all 3 groups, did not correlate with the tumor-inhibitory effect. These results suggest that uracil in the tumor may play an important role in the metabolism of fluorinated pyrimidines, and that exogeneously administered uracil may decrease the amounts of uracil and TS in the tumor, and subsequently cause 5-FU accumulation.
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PMID:Relationship of in vivo antitumor activities of fluorinated pyrimidines to thymidylate synthase activity and intratumoral concentrations of 5-fluorouracil and uracil. 206 15

We studied the relationship between antitumor efficacy of UFT, which is a most widely used drug among fluorinated pyrimidines recently, and its effect on the content and the inhibition rate of thymidylate synthase (TS) in 15 human tumor xenografts derived from stomach, colon, breast and pancreatic cancer patients. There was a linear relationship between the content of TS and tumor mass doubling time (MDT). It may be shown that TS content reflects the growth rate of tumor cells. It should be stressed that tumor growth inhibition rate (TGIR), induced by UFT, correlated well with the inhibition of TS (TSI), particularly in the stomach and breast cancer. These results demonstrate that the measurement of inhibition rate of TS is important for the prediction and evaluation of clinical efficacy of UFT.
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PMID:[Relationship between antitumor activity and the inhibition of thymidylate synthase after oral administration of UFT in nude mice bearing human tumor]. 210 11

Treatment of Ehrlich ascites tumor cells with 2-difluoromethylornithine (F2MeOrn), an enzyme-activated irreversible inhibitor of ornithine decarboxylase, resulted in depleted putrescine and spermidine content, and reduced growth rate. We have previously shown that adenine ribonucleotide levels are substantially increased in these polyamine-depleted cells. The present paper addresses the question whether the elevated ATP pool is accompanied by a concomitant increase in the dATP pool. If this is the case, the observed growth inhibition could be explained by the well-known dATP-mediated feedback inhibition of ribonucleotide reductase. We found that dNTP pools were not unbalanced and that dNTP synthesis was not arrested in polyamine-depleted cells. Moreover, the dNTP content and the activity of ribonucleotide reductase (CDP reduction) and thymidylate synthase, remained elevated despite the fact that the cells were inhibited in their growth by F2MeOrn treatment. Incorporation of a radiolabeled precursor into DNA was initially lower in F2MeOrn-treated. cells than in control cells. However, while incorporation of a radiolabeled precursor into DNA decreased markedly in plateau-phase control cells, it remained at a higher level in cells inhibited in growth by polyamine depletion. This discrepancy may be explained by the fact that polyamine-depleted cells accumulated in the S phase, and that they had an increased content of acid-soluble radiolabeled DNA precursor. Our data indicate that polyamine depletion adversely affects the DNA synthetic machinery by reducing the rate of elongation.
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PMID:Implications for a reduced DNA-elongation rate in polyamine-depleted cells. 211 38

The thymidylate synthase (TS) content of tumor tissue was assayed and the levels of 5-fluorouracil (5-Fu) in serum and tumor tissue were determined in 21 patients with cervical cancer who were treated with UFT, a fluorinated pyrimidine. Subrenal capsule assay, a predictive tumor sensitivity test, was conducted concurrently on cervical tumor samples. TS inhibition and serum and tissue 5-Fu levels widely varied between both samples. Investigation of the relationship between the tumor growth inhibition rate determined by subrenal capsule assay and the above parameters (TS inhibition, serum and tissue 5-Fu levels) showed that TS inhibition and tumor growth inhibition were well correlated (r = 0.73). This suggests that a TS inhibition assay in tumor tissue can be a useful predictive test for tumor sensitivity of fluorinated pyrimidines.
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PMID:Thymidylate synthase inhibition as a predictor of tumor sensitivity of fluorinated pyrimidines. 211 22

The effects of preoperative treatment by continuous intravenous infusion of Tegafur, the antagonist of DNA synthesis, were histopathologically studied in 34 patients with gastric cancer. Histologically the treatment was found to be effective in 41.2% of patients with cancer invasion in the mucosa, 58.8% in the submucosa, 61.3% in the muscularis propria, 59.3% in the subserosa and 86.9% of those with metastatic lymph nodes. The treatment was effective, when assessed in terms of the histological type of cancer, in 90.9% of cancers of the differentiated type (papillary adenocarcinoma, well differentiated tubular adenocarcinoma and moderately differentiated tubular adenocarcinoma) and 47.8% of those of the poorly differentiated type (poorly differentiated adenocarcinoma, mucinous adenocarcinoma and signet-ring cell carcinoma), showing a higher rate of efficacy in the differentiated type cancers. Meanwhile, even among patients with cancer of poorly differentiated type, a high efficacy rate (90.0%) was found in those with metastatic cancer of the lymph nodes. No relationship was found between the total doses of Tegafur and histological effects. There was a tendency, however, for a higher frequency of a good response in patients administered more than 4,000 mg of Tegafur. In the patients with a histologically positive effect, 5-FU concentration in the tumor tissue was higher than 0.071 microgram/g. However, some patients showed no response despite a high concentration. This finding suggested that sensitivity to 5-FU and 5-FU metabolism vary depending on the tumor. The inhibitory effect of Tegafur on DNA synthesis is produced through inhibition of thymidylate synthase (TS) by the Tegafur metabolite FdUMP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Histopathological studies on antitumor effect of tegafur administered by continuous intravenous infusion]. 211 40

Peritoneal cells were derived from a patient (PK) with adenocarcinoma of the colon during the course of cisplatin/5-fluorouracil (5-FUra) treatment. Resistance to cisplatin and 5-FUra, characterized by a lack of response to chemotherapy and continued growth of the tumor, was concomitantly associated with a 2-4-fold increase in DNA copy number for dTMP synthase and dihydrofolate reductase. There was a corresponding amplification in DNA copy number of the c-myc (2X), H-ras (4X), and c-fos (15X) oncogenes. Cytogenetic studies revealed an iso (13q) chromosome, but failed to show any double minutes or homogeneously staining regions. In addition, drug-resistant tumor cells from PK and another patient (HG) displayed enhanced expression of dTMP synthase, c-fos and DNA polymerase beta when compared to normal colon tissue and the HCT8 human colon carcinoma cell line. These results suggest that elevated oncogene DNA and gene expression may be involved in the development of cisplatin resistance.
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PMID:Differential oncogene amplification in tumor cells from a patient treated with cisplatin and 5-fluorouracil. 214 97

Although 5-fluorouracil (FUra) is one of the most effective cytotoxic agents in the treatment of various solid tumors (carcinomas of the gastro-intestinal tract, breast, head and neck), remissions occur in only 20 to 30% of cases and usually are of short duration. Recently, preclinical studies have shown that the antitumor activity of FUra can be potentiated by modulating the metabolism of this drug by using other substances, in particular antifolates of folates. Pretreatment with antifolates may, by blocking de novo purine biosynthesis and consequently increasing phosphoribosyl pyrophosphate (PRPP) pools, enhance the conversion of FUra to active fluoronucleotide pools via orotate phosphoribosyltransferase. Methotrexate (MTX) pretreatment may also enhance binding of the fluoropyrimidine inhibitor, 5-fluodeoxyuridylate (FdUMP), to the target enzyme, thymidylate synthase (TS), indirectly by increasing dihydrofolate polyglutamates or directly, as MTX polyglutamates, by enhancing the formation of ternary complexes with FdUMP and TS. Exogenous folates, in particular 5-formyltetrahydrofolate (folinate, leucovorin, LV), can, by raising the intracellular levels of 5, 10-methylenetetrahydrofolate, lead to increased formation and stabilization of the ternary complex formed by TS, the folate coenzyme, and FdUMP. In vitro studies have also shown potentiation of FUra cytotoxicity by antifolates and folates against human lymphoblastic leukemia cell lines. Thus, while FUra may have little or no single agent activity in leukemias and lymphomas, it may be converted to an active drug in these neoplasms by appropriate modulation. Clinical studies of sequential MTX-FUra or combined LV-FUra based upon experimental tumor results reviewed herein, are warranted.
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PMID:Biochemical modulation of fluoropyrimidines by antifolates and folates in an in vitro model of human leukemia. 214 14

Leucovorin (LV) increased the growth inhibition produced by iododeoxyuridine (IdUrd), a halogenated analogue of thymidine, in a murine tumor cell line (L1210) and three human tumor cell lines (HL-60, HT-29, and MCF-7). This increased growth inhibition was associated with increased incorporation of IdUrd into DNA. Consistent with previous reports, IdUrd (as iododeoxyuridine monophosphate) inhibited thymidylate synthase (TS) and was dehalogenated intracellularly by TS to generate thymidine nucleotides. In all four cell lines, LV decreased the dehalogenation of IdUrd, producing a 3-fold increase in the labeled iododeoxyuridine triphosphate/dTTP ratios in cytoplasm and labeled IdUrd/thymidine in DNA derived from tritiated IdUrd. In intact L1210 cells, apparent TS activity was inhibited 50% by 3 microM IdUrd alone and 75% by the combination of 3 microM IdUrd and 20 microM LV. Apparent TS activity was unchanged with 20 microM LV alone. In all cell lines except HL-60, the ratios of labeled iododeoxyuridine triphosphate/dTTP derived from tritiated IdUrd were 3-fold lower than the labeled IdUrd/thymidine ratios in DNA. This observation suggests that replicative DNA polymerases preferentially incorporate iododeoxyuridine triphosphate into DNA compared to the endogenous substrate dTTP. This preferential incorporation was independent of the effect of LV. These novel findings suggested that a potential mechanism for the effects of LV on IdUrd was increased inhibition of TS analogous to the interaction between fluoropyrimidines and LV. Enzyme inhibition studies using L1210 cell extracts showed that iododeoxyuridine monophosphate was a weak inhibitor of TS (Ki greater than 10 microM) when compared to 5-fluorodeoxyuridine monophosphate (Ki less than 10 nM). Despite the major differences in potency of these two halogenated pyrimidines, LV appears to modulate the activity of IdUrd as well as 5-fluorodeoxyuridine. LV may provide a clinically useful approach to improve the radiosensitizing and/or cytotoxic properties of IdUrd.
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PMID:Effects of leucovorin on idoxuridine cytotoxicity and DNA incorporation. 220 28


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