Thymidylate synthetase activity and fluorouracil sensitivity of human colonic cancer and normal mucosal tissue preparations

Wolberg, William H.; Morin, Jean‐Frédéric

doi:10.1002/1097-0142(19810315)47:6<1313::aid-cncr2820470613>3.0.co;2-o

Cited by 12 publications

(5 citation statements)

References 14 publications

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“…Concerning TS, the increase in average activity in colon tumors as compared to normal tissues, as well as the very high inter-tumoral variations, are in agreement with previously published results (Wolberg and Morin, 1981).…”

Section: Enzyme Activities In Normal Mucosae and In Primary And Xenogsupporting

confidence: 92%

“…To characterize human colorectal tumors, numerous studies have been focused upon enzyme activities (Ahmed et al, 1982;Ahmed, 1984;Denton et al, 1982;Finan et al, 1984;Lipkin, 1977;Weber et al, 1978Weber et al, , 1980Weber et al, , 1981Wolberg and Morin, 1981). These investigations concerned, in particular, the pyrimidine nucleotide pathway, since 5-fluorouracil remains the most effective single therapeutic agent in these tumors.…”

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confidence: 99%

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Pyrimidine nucleotide metabolism in human colon carcinomas: Comparison of normal tissues, primary tumors and xenografts

Luccioni

Beaumatin

Bardot

et al. 1994

Intl Journal of Cancer

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The activities of 5 enzymes involved in the pyrimidine metabolism were measured in xenografts of 8 human colon adenocarcinomas and in the corresponding primary tumors and normal tissues. The enzymes studied were thymidine kinase, thymidine phosphorylase, uridine kinase, uridine phosphorylase and thymidylate synthase. With the exception of the phosphorylases in one tumor, all enzyme activities were higher in primary tumors than in the corresponding normal tissues. The average activities of thymidine kinase and thymidylate synthase were of the same order of magnitude in xenografts and in primary tumors. The uridine metabolizing enzymes tend to have a higher activity in xenografts than in primary tumors. The most consistent and significant change was a sharp decrease in thymidine phosphorylase activity in xenografts as compared to primary tumors. Whether or not the difference in thymidine phosphorylase activity between xenografts and primary tumors is related to the contribution of non-cancerous cells in primary tumors remains to be determined. However, these results raise questions concerning the representativeness of xenografts with reference to primary tumors and suggest that care should be taken in the application of this model.

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Section: Enzyme Activities In Normal Mucosae and In Primary And Xenogsupporting

confidence: 92%

mentioning

confidence: 99%

Pyrimidine nucleotide metabolism in human colon carcinomas: Comparison of normal tissues, primary tumors and xenografts

Luccioni

Beaumatin

Bardot

et al. 1994

Intl Journal of Cancer

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“…2 TS catalyzes the reductive methylation of dUMP by 5,10-methylenetetrahydrofolate to form dTNP, which is a critical reaction for cell proliferation. 3 Early in vitro studies have demonstrated more resistance to 5-FU of cell lines with high TS expression 4 or transfected with wild-type TS cDNA. 5 A number of studies have been published indicating that patients with high tumor levels of TS are unlikely to respond to infusion treatment with 5-FU, whereas patients with low levels have response rates that are higher than expected.…”

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confidence: 99%

Single nucleotide polymorphism in the 5′ tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil‐based chemotherapy in advanced colorectal cancer patients

Marcuello

Altés

Río

et al. 2004

Intl Journal of Cancer

132

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Thymidylate synthase (TS) is the primary target of 5-fluorouracil (5-FU).A VNTR polymorphism in the TS promoter region is associated with the efficacy of 5-FU-based chemotherapy in colorectal cancer. A common G>C SNP at the 12th nucleotide of the second repeat in the TS*3 alleles has been recently described. The combination of SNP and VNTR allows the definition of 3 TS alleles: *2, *3G and *3C. The aim of our study was to evaluate the predictive value of clinical response and survival of these new defined TS alleles. TS genotypes of 89 patients diagnosed with metastatic colorectal cancer and undergoing 5-FU-based chemotherapy were carried out. The clinical outcome was evaluated according to the genotype (high expression genotype: *2R/*3G; *3C/*3G; *3G/*3G; and low expression genotype: *2R/*2R; *2R/*3C; *3C/*3C. A higher overall response was observed in the group of patients with a low expression genotype (p ‫؍‬ 0.035). The probability of achieving a clinical response of patients with a low expression-related genotype was 2.9 higher than that of the other group (95% CI ‫؍‬ 1.03-5.6, p ‫؍‬ 0.04). The median time to progression was 12 months and 9 months in the low and high expression groups, respectively (p ‫؍‬ 0.07, log rank test). Overall survival was significantly longer in the low expression group. In this group the median OS was not achieved at 50 months of follow-up in contrast to the 20 months observed in the high expression group (p ‫؍‬ 0.03). TS genotype was an independent predictor of progression-free and overall survival in the Cox regression models after adjustment to the other clinical variables. The selection of patients who are likely to respond to 5-FU therapy may be considerably improved if the TS genotype were to include both the VNTR and the SNP located within the promoter region of the gene. © 2004 Wiley-Liss, Inc. Key words: 5-FU resistance; TS-polymorphism; colorectal cancer; fluoropyrimidine chemotherapyA high proportion of colorectal cancer, which is a leading cause of cancer-related morbidity and mortality in the Western world, is diagnosed at advanced stages when chemotherapy is required for its management. 5-Fluorouracil (5-FU) is a folate-pathway inhibitor that has been available for 50 years, and continues to be a mainstay of treatment of advanced disease. 1 This drug is a fluoropyrimidine that, on activation to the nucleotide form, develops a stable complex with thymidylate synthase (TS), inhibiting the activity of the enzyme. 2 TS catalyzes the reductive methylation of dUMP by 5,10-methylenetetrahydrofolate to form dTNP, which is a critical reaction for cell proliferation. 3 Early in vitro studies have demonstrated more resistance to 5-FU of cell lines with high TS expression 4 or transfected with wild-type TS cDNA. 5 A number of studies have been published indicating that patients with high tumor levels of TS are unlikely to respond to infusion treatment with 5-FU, whereas patients with low levels have response rates that are higher than expected. 6 -13 The agreement between these...

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“…Thus 5-FU is cycle specific in that sense lhal it is selectively toxic to proliferating cells. Other factors such as a difference in the ability of cells lo convert FU to FdUMP (5) and a major difference in pyrimidine nucleotide metabolism (6) might also be of importance for the dif ferential sensitivity, aJthough these factors were not investigated.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of 5-fluorouracil on human skin melanocytes and malignant melanoma cells in vitro

Tsuji,

Karasek

1986

Acta Derm Venereol

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We have observed differential effects of the cytotoxicity of 5-fluorouracil (5-FU) on human skin melanocytes and malignant melanoma cells in vitro. In the absence of 5-FU the melanoma cells multiplied much more rapidly than the melanocytes. With a 7-day exposure of 5-FU (1.92 X 10(-5) to 3.84 X 10(-4) M) all the melanoma cells died by 5 W, while even two times longer exposure (a 14-day exposure) of 5-FU the melanocytes survived till 6 W and increased at the lower concentration. In the presence of 5-FU there was a different compensatory increase in [3H] thymidine incorporation between the two cell types. That is, compared with the large increase observed in the incorporation by the melanoma cells, a small increase in the incorporation by the melanocytes was observed. The reason for these differential effects of 5-FU may be the difference in the cell cycle and the post-injury cell renewal of the two cell types.

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Thymidylate synthetase activity and fluorouracil sensitivity of human colonic cancer and normal mucosal tissue preparations

Cited by 12 publications

References 14 publications

Pyrimidine nucleotide metabolism in human colon carcinomas: Comparison of normal tissues, primary tumors and xenografts

Pyrimidine nucleotide metabolism in human colon carcinomas: Comparison of normal tissues, primary tumors and xenografts

Single nucleotide polymorphism in the 5′ tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil‐based chemotherapy in advanced colorectal cancer patients

Differential effects of 5-fluorouracil on human skin melanocytes and malignant melanoma cells in vitro

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