Binding of 5-fluorodeoxyuridylate to thymidylate synthase in human colon adenocarcinoma xenografts

Houghton, Janet A.; Torrance, Pamela M.; Radparvar, Saeed; Williams, Larry G.; Houghton, Peter J.

doi:10.1016/0277-5379(86)90119-7

Cited by 20 publications

(4 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thymidylate is the necessary precursor of thymidine triphosphate (dTTP) that is an essential precursor for DNA replication and repair [245,246]. The 5-FU metabolite FdUMP, together with CH2THF as a co-factor, binds to TS to form a covalently bound ternary complex, thereby blocking of the normal substrate dUMP binding to inhibit dTMP synthesis [247]. Depletion of dTMP leads consequent depletion of dTTP, resulting in perturbations in the levels of dATP, dGTP and dCTP through various feedback mechanisms to disrupt DNA replication and repair.…”

Section: Epigenetic Regulation Of Chemosistance In Crcmentioning

confidence: 99%

Epigenetics and Colorectal Cancer Pathogenesis

Bardhan

Liu

2013

Cancers

210

145

View full text Add to dashboard Cite

Colorectal cancer (CRC) develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy.

show abstract

Section: Epigenetic Regulation Of Chemosistance In Crcmentioning

confidence: 99%

Epigenetics and Colorectal Cancer Pathogenesis

Bardhan

Liu

2013

Cancers

210

145

View full text Add to dashboard Cite

show abstract

“…It has also been observed that an increase in the intracellular pool of reduced folates following exposure to folinic acid enhances 5-FU antitumor activity [44,45]. This is due to an increased inhibition of TS enzyme activity via the formation of a covalent ternary complex among the active 5-FU metabolite 5-fluoro-2'-deoxyuridine-5'-monophosphate, TS and the 5,10-methylene tetrahydrofolate cofactor [3,4,46]. This ultimately leads to greater sensitivity to 5-FU [47] and improves response rate and overall survival in colorectal cancer patients compared with 5-FU alone [48].…”

Section: Article In Pressmentioning

confidence: 99%

Thymidylate synthase expression and genotype have no major impact on the clinical outcome of colorectal cancer patients treated with 5-fluorouracil

Vignoli

Nobili

Napoli

et al. 2011

Pharmacological Research

View full text Add to dashboard Cite

The results obtained in this pilot study indicate that the number of 5' UTR repeats is the major genetic determinant of TS expression. The lack of association with other polymorphisms might be partially explained by the existence of linkage disequilibrium in the TS gene. Our data support the growing evidence that TS control may require multiple mechanisms acting in close coordination with one another and suggest that TS genotyping alone in tumor samples is not sufficient to accurately predict response to 5-FU.

show abstract

“…3, and the relationship between t 89 for dissociation and the concentration of [6RS]CH2-H4PteGIu for 3 aden0carcinoma lines is shown in Fig. 4 [17]. These data indicate that expanding the pool of CH 2-H4PteGlu, or its polyglutamate derivatives, may significantly stabilize the inhibitory complex in vivo.…”

Section: Natural Resistance Of Human Colorectal Xenografts To 5-fluormentioning

confidence: 84%

“…( x ) 100, ( 9 ) 50; ( [] ) 25; ( 9 ) 10; ( 9 5; (o) 1; (o)0/~M [6RS]CH2-HnPteGlu. Source: Houghton et aL[17]. ELC 2 xenografts.…”

mentioning

confidence: 99%

Biochemical mechanisms in colon xenografts: Thymidylate synthase as a target for therapy

Houghton

Hazelton

et al. 1989

Invest New Drugs

View full text Add to dashboard Cite

Growth of human adenocarcinomas of the colon and rectum in immunoincompetent mice has allowed for a greater understanding of the interaction of 5-fluorouracil, its metabolism, and mechanism(s) of cytotoxicity under conditions of tumor growth in situ. Conversely, this agent has proven to be a useful tool in defining metabolic characteristics in human colon adenocarcinomas. Analysis of tumor sensitivity to 5-fluorouracil (FUra),5-fluorouridine (FUrd) and 5-fluoro-2'-deoxyuridine (FdUrd) suggests that growth inhibition in vivo is related to a DNA-directed event. Resistance, de novo appears to be a consequence of relatively transient inhibition of the target enzyme thymidylate synthase (dTMP-synthase), which may be a consequence of low concentrations of 5,10-methylenetetrahydrofolate (CH2-H4PteGlu) or its polyglutamate forms within tumor cells in situ. In order to study the relationship between inhibition of dTMP-synthase and growth inhibition, mutant cells deficient in their ability to salvage dThd have been selected, and grown as xenografts. Data suggest that transient inhibition of dTMP-synthase and not dThd salvage is responsible for resistance de novo, and that prolonged inhibition of dTMP-synthase would be a lethal event in vivo. This would predict that a cell lacking dTMP-synthase activity would not be tumorigenic. This has been tested directly by selecting clones of GC3 colon adenocarcinoma cells deficient in dTMP-synthase (TS-) activity. Preliminary data indicate that each of 3 TS- clones is tumorigenic in athymic nude mice. The importance of dTMP-synthase as a target for drug development is discussed with respect to these findings.

show abstract

Binding of 5-fluorodeoxyuridylate to thymidylate synthase in human colon adenocarcinoma xenografts

Cited by 20 publications

References 10 publications

Epigenetics and Colorectal Cancer Pathogenesis

Epigenetics and Colorectal Cancer Pathogenesis

Thymidylate synthase expression and genotype have no major impact on the clinical outcome of colorectal cancer patients treated with 5-fluorouracil

Biochemical mechanisms in colon xenografts: Thymidylate synthase as a target for therapy

Contact Info

Product

Resources

About