Activity and substrate specificity of pyrimidine phosphorylases and their role in fluoropyrimidine sensitivity in colon cancer cell lines

Temmink, Olaf H.; Bruin, Michiel de; Turksma, Annelies W.; Cricca, Silvia; Laan, A.C.; Peters, Godefridus J.

doi:10.1016/j.biocel.2006.10.009

Cited by 28 publications

(34 citation statements)

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“…Higher levels of 5-FU are thus produced within tumours with minimal exposure of healthy tissue to 5-FU [51]. It is important to note that several studies have underlined the critical role that UP plays in converting 5'd5-FUrd to 5-FU, which some studies have suggested that it might be more important than that of TP [54,55]. The preferential activation of capecitabine in tumour tissue and its dependence on TP was shown in a study of 19 patients with colorectal cancer requiring surgical resection for primary tumour and/or liver metastases that were treated with capecitabine for 5-7 days prior to surgery [56].…”

Section: Tp In the Metabolism Of Fluoropyrimidinesmentioning

confidence: 99%

“…In 2007, Temmink et al investigated the substrate specificity of TP and UP for thymidine, uridine and 5-FU in colon cancer patients. They concluded that overlapping substrate specificity was found for TP and UP and both enzymes are responsible for converting thymidine and uridine [55]. TP overexpression in cell culture and xenograft models had been shown to increase sensitivity to 5-FU due to enhanced formation of FdUMP [reviewed in 3,51].…”

Section: Tp In the Metabolism Of Fluoropyrimidinesmentioning

confidence: 99%

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Thymidine Phosphorylase in Cancer; Enemy or Friend?

Elamin

Rafee

Osman

et al. 2015

Cancer Microenvironment

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Thymidine phosphorylase (TP) is a nucleoside metabolism enzyme that plays an important role in the pyrimidine pathway.TP catalyzes the conversion of thymidine to thymine and 2-deoxy-α-D-ribose-1-phosphate (dRib-1-P). Although this reaction is reversible, the main metabolic function of TP is catabolic. TP is identical to the angiogenic factor platelet-derived endothelial-cell growth factor (PD-ECGF). TP is overexpressed in several human cancers in response to cellular stressful conditions like hypoxia, acidosis, chemotherapy and radiotherapy. TP has been shown to promote tumor angiogenesis, invasion, metastasis, evasion of the immuneresponse and resistance to apoptosis. Some of the biological effects of TP are dependent on its enzymatic activity, while others are mediated through cytokines like interleukin 10 (IL-10), basic fibroblast growth factor (bFGF) and tumour necrosis factor α (TNFα). Interestingly, TP also plays a role in cancer treatment through its role in the conversion of the oral fluoropyrimidine capecitabine into its active form 5-FU. TP is a predictive marker for fluoropyrimidine response. Given its various biological functions in cancer progression, TP is a promising target in cancer treatment. Further translational research is required in this area.

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Section: Tp In the Metabolism Of Fluoropyrimidinesmentioning

confidence: 99%

Section: Tp In the Metabolism Of Fluoropyrimidinesmentioning

confidence: 99%

Thymidine Phosphorylase in Cancer; Enemy or Friend?

Elamin

Rafee

Osman

et al. 2015

Cancer Microenvironment

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“…This is an advantage for the oral 5FU prodrug capecitabine ((+)-pentyl 1-(5-deoxy-β-D-ribofuranosyl)-5-fluoro-1,2-dihydro-2-oxo-4-pyrimidinecarbamate) [Van Cutsem et al 2001;Hoff et al 2001], which is activated by PDECGF/ TP and for which a low expression negatively influences therapeutic outcome of capecitabinebased chemotherapy [Ackland and Peters, 1999]. However, activation of the capecitabine intermediate 5-fluoro-5'-deoxyuridine (5'DFUR) to 5FU can also be mediated by UP [Cao and Pizzorno, 2004;Temmink et al 2006aTemmink et al , 2007a, but TPI is a poor inhibitor of UP . Since TFT is a poor substrate for UP, a high activity of UP will unlikely affect the efficacy of TFT.…”

Section: Tumor Angiogenesismentioning

confidence: 99%

Therapeutic potential of TAS-102 in the treatment of gastrointestinal malignancies

Peters

2015

Ther Adv Med Oncol

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Fluoropyrimidines form the mainstay in treatment of gastrointestinal malignancies. For decades 5-fluorouracil (5FU), was the major fluoropyrimidine. Currently it is usually given in a combination with leucovorin and oxaliplatin, i.e. FOLFOX, or irinotecan, i.e. FOLFIRI, or all three, i.e. FOLFIRINOX, but gradually it has been replaced by oral fluoropyrimidine prodrug formulations, such as tegafur-uracil and S-1 (both contain ftorafur), and capecitabine (Xeloda®). Novel drugs such as the antivascular endothelial growth factor antibody, bevacizumab, and the anti-epidermal growth factor receptor antibody, cetuximab, are often combined with one of these treatment options. However, when resistance emerged, no alternatives were available. TAS-102, a combination of trifluorothymidine and the thymidine phosphorylase inhibitor TPI in a 1:0.5 ratio, is a novel oral formulation, which is active in 5FU-resistant models, both in vitro and in xenograft models. In addition to inhibition of thymidylate synthase, the major mechanism of action of classical fluoropyrimidines, TAS-102's major mechanism of action is incorporation into DNA, thereby causing DNA damage. TAS-102 also follows an alternative activation pathway via thymidine kinase, and is not a substrate for dihydropyrimidine dehydrogenase. All together this explains the efficacy in 5FU-resistant models. In early clinical studies, the twice-daily schedule (5 days on, 2 days rest) for 2 weeks every 4 weeks, led to a significant disease control rate in various malignancies. This schedule showed consistent activity in two randomized trials on fluoropyrimidine refractory colorectal cancer patients, reflected by an increase of 2-3 months in overall survival in the TAS-102 group compared with placebo. Considering the impressive preclinical potential of various combinations TAS-102 has the promise to become an alternative for 5FU-resistant cancer.

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Section: Introductionmentioning

confidence: 99%

“…It may be converted to FUMP either directly by orotate phosphoribosyltranferase or by the sequential actions of uridine phosphorylase and uridine kinase. FUMP may be converted to FUDP and then to FUTP, INTERNATIONAL JOURNAL OF ONCOLOGY 36: 1193-1200, 2010 The role of thymidine phosphorylase in the induction of early growth response protein-1 and thrombospondin-1 by 5-fluorouracil in human cancer carcinoma cells Abbreviations: TP, thymidine phosphorylase; PD-ECGF, plateletderived endothelial cell growth factor; 5-FU, 5-fluorouracil; TPI, thymidine phosphorylase inhibitor; LV, leucovorin; PBS, phosphatebuffered saline; DAB, diaminobenzidine; TS, thymidylate synthetase; FdUMP, 5-fluoro-deoxyuridine-monophosphate; MTT, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; HPLC, high performance liquid chromatography; PARP, poly (ADP-ribose) polymerase; TSP-1, thrombospondin-1; Egr-1, early growth response protein-1; aPAI-1, plasminogen activator inhibitor; 5'-DFUR, 5'-deoxy-5-fluorouridine …”

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confidence: 99%

The role of thymidine phosphorylase in the induction of early growth response protein-1 and thrombospondin-1 by 5-fluorouracil in human cancer carcinoma cells

Akiyama¹

2010

Int J Oncol

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Abstract. Thymidine phosphorylase (TP) is an enzyme involved in reversible conversion of thymidine to thymine. TP is identical to an angiogenic factor, pletelet-derived endothelial cell growth factor (PD-ECGF) and the expression levels of TP in a variety of malignant tumors were higher than the adjacent non-neoplastic tissues. To investigate the molecular basis for the effect of TP on the metabolic process and the anticancer effect of 5-fluorouracil (5-FU), human gastric carcinoma AZ521 cells and epidermoid carcinoma KB cells were transfected with TP cDNA, and AZ521/TP and KB/ TP were cloned. AZ521/TP and KB/TP cells overexpressed TP and were more sensitive to 5-FU than the counterpart parental cells. TPI, a newly synthesized inhibitor for TP (Ki=2.36x10 -9 M), decreased the sensitivity to 5-FU of the TP expressing cells but not of the parental cells. 5-Formyltetrahydrofolate (leucovorin; LV) stabilized the complex of thymidylate synthase (TS) and 5-fluoro-deoxyuridinemonophosphate (FdUMP), increased the sensitivity to 5-FU of TP expressing AZ521 cells, but not of the parental cells. The levels of FdUMP in TP expressing cells were significantly higher than in parental cells and TPI considerably decreased FdUMP to the level comparable to that in the parental cells. 5-FU increased the expression of early growth response protein-1 (Egr-1) and an angiogenesis inhibitor, thrombospondin-1 (TSP-1), in KB/TP cells but only slightly in KB/CV cells, if any. TPI attenuated the induction of Egr-1 and TSP-1 mRNA by 5-FU, while LV increased the expression of Egr-1 and TSP-1 mRNA in KB/TP cells. These findings demonstrate that the TP has a principal role in the production of FdUMP and the enhanced responses to 5-FU by leucovorin in TP-overexpressing KB and AZ521 cells, and FdUMP but not FUTP is implicated in the induction of Egr-1 and TSP-1 in KB cells. IntroductionThymidine phosphorylase (TP) catalyzes the reversible phosphorolysis of thymidine, deoxyuridine, and their analogues to their respective bases and 2-deoxyribose-1-phosphate (1-3). It also catalyzes deoxyribosyltransfer from one deoxynucleotide to another base, to form a second deoxyuridine (4-6). Recent studies showed that TP is expressed in a wide variety of solid tumors (7-13), but the role of TP in tumor proliferation was unknown. We have found that TP is identical to an angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF), and the enzymatic activity of TP is need for the angiogenesis by TP (14-16). TP is also considered to activate some pyrimidine antimetabolites (17-19). 5-Fluorouracil (5-FU) was developed as a potential anti-tumor drug (20), and reportedly activated through three alternative routes. It may be converted to FUMP either directly by orotate phosphoribosyltranferase or by the sequential actions of uridine phosphorylase and uridine kinase. FUMP may be converted to FUDP and then to FUTP, INTERNATIONAL JOURNAL OF ONCOLOGY 36: 1193-1200, 2010 The role of thymidine phosphorylase in the induction of early growth response protein-1...

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Activity and substrate specificity of pyrimidine phosphorylases and their role in fluoropyrimidine sensitivity in colon cancer cell lines

Cited by 28 publications

References 38 publications

Thymidine Phosphorylase in Cancer; Enemy or Friend?

Thymidine Phosphorylase in Cancer; Enemy or Friend?

Therapeutic potential of TAS-102 in the treatment of gastrointestinal malignancies

The role of thymidine phosphorylase in the induction of early growth response protein-1 and thrombospondin-1 by 5-fluorouracil in human cancer carcinoma cells

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