Thymidine Phosphorylase Activity Associated with Platelet-Derived Endothelial Cell Growth Factor1

Sumizawa, Tomoyuki; Furukawa, Tatsuhiko; Haraguchi, Masanobu; Yoshimura, Akihiko; Takeyasu, Akira; Ishizawa, Minoru; Yamada, Yuji; Akiyama, Shin Ichi

doi:10.1093/oxfordjournals.jbchem.a124146

Cited by 121 publications

(66 citation statements)

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“…In vivo, TFT is very dependent on TP activity, since adding TPI enhances bioavailability of TFT (Emura et al, 2005), which may favour the combination OHP-TFT, possibly leading to more DNA damage in cells and higher cytotoxicity. Secondly, TP is also known as PD-ECGF (Moghaddam and Bicknell, 1992;Sumizawa et al, 1993), which has stimulating properties on blood vessel formation in solid tumours (Takahashi et al, 1998). Previous studies showed that TPI inhibits blood vessel formation, thereby increasing apoptosis (Matsushita et al, 1999) and suppressing the formation of metastases (Takao et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Mechanism of trifluorothymidine potentiation of oxaliplatin-induced cytotoxicity to colorectal cancer cells

et al. 2007

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Oxaliplatin (OHP) is an anticancer agent that acts by formation of Platinum-DNA (Pt-DNA) adducts resulting in DNA-strand breaks and is used for the treatment of colorectal cancer. The pyrimidine analog trifluorothymidine (TFT) forms together with a thymidine phosphorylase inhibitor (TPI) the anticancer drug formulation TAS-102, in which TPI enhances the bioavailability of TFT in vivo. In this in vitro study the combined cytotoxic effects of OHP with TFT were investigated in human colorectal cancer cells as a model for TAS-102 combinations. In a panel of five colon cancer cell lines (WiDr, H630, Colo320, SNU-C4 and SW1116) we evaluated the OHP-TFT drug combinations using the multiple drug -effect analysis with CalcuSyn software, in which the combination index (CI) indicates synergism (CIo0.9), additivity (CI ¼ 0.9 -1.1) or antagonism (CI41.1). Drug target analysis was used for WiDr, H630 and SW1116 to investigate whether there was an increase in Pt-DNA adduct formation, DNA damage induction, cell cycle delay and apoptosis. Trifluorothymidine combined with OHP resulted in synergism for all cell lines (all CIo0.9). This was irrespective of schedule in which either one of the drugs was kept at a constant concentration (using variable drug ratio) or when the two drugs were added in a 1 : 1 IC 50 -based molar ratio. Synergism could be increased for WiDr using sequential drug treatment schedules. Trifluorothymidine increased Pt-DNA adduct formation significantly in H630 and SW1116 (14.4 and 99.1%, respectively; Po0.05). Platinum-DNA adducts were retained best in SW1116 in the presence of TFT. More DNA-strand breaks were induced in SW1116 and the combination increased DNA damage induction (420%) compared with OHP alone. Exposure to the drugs induced a clear cell-cycle S-phase arrest, but was dose schedule and cell line dependent. Trifluorothymidine (TFT) and OHP both induced apoptosis, which increased significantly for WiDr and SW1116 after TFT -OHP exposure (18.8 and 20.6% respectively; Po0.05). The basal protein levels of ERCC1 DNA repair enzyme were not related to the DNA damage that was induced in the cell lines. In conclusion, the combination of TFT with the DNA synthesis inhibitor OHP induces synergism in colorectal cancer cells, but is dependent on the dose and treatment schedule used.

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Section: Discussionmentioning

confidence: 99%

Mechanism of trifluorothymidine potentiation of oxaliplatin-induced cytotoxicity to colorectal cancer cells

et al. 2007

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“…It is an angiogenic factor that was found to be chemotactic for endothelial cells in vitro and to induce neovascularization in several in vivo assays (Miyazono et al, 1987;Ishikawa et al, 1989;Sumizawa et al, 1993;Finnis et al, 1993). Studies have shown that TP expression was frequently elevated in human solid tumors, including colorectal cancers, where its expression was correlated with increased tumor microvessel density, increased tumor invasion and metastasis, and shorter patient survival time (Takebayashi et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

The Sp1 transcription factor contributes to the tumor necrosis factor-induced expression of the angiogenic factor thymidine phosphorylase in human colon carcinoma cells

2002

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Thymidine phosphorylase (TP; also known as plateletderived endothelial cell growth factor, PD-ECGF) is an angiogenic factor that is chemotactic for endothelial cells and has been found to induce neovascularization in vivo. TP is frequently overexpressed in human solid tumors, where its expression has been correlated with increased tumor microvessel density, invasion, and metastasis, and shorter patient survival. In this report, TP activity in the WiDr colon carcinoma cell line was found to be induced 100-fold by tumor necrosis factor (TNFa), a secretory product of activated macrophages that has indirect angiogenic activities. Increased TP activity was accompanied by increased TP mRNA levels and without an increase in mRNA stability. TNFa-induced TP mRNA levels were reduced by mithramycin, a DNA-binding transcription inhibitor specific for GC-rich sequences. Transcriptional regulation by TNFa was confirmed by transient transfection of WiDr with upstream TP sequences in a luciferase reporter construct. Deletion analysis of the reporter pinpointed two regions of the TP promoter with regulatory elements for both TNFainducible and basal expression, and they contained, respectively, three and one consensus binding sites for the Sp1-family of transcription factors. One additional region contributed only to basal TP expression, and it contained three Sp1 sites. TNFa-induced TP expression decreased when point mutations were made in three of the four Sp1 sites postulated to contribute to both basal and TNFa-inducible expression. Electrophoretic mobility shift assays further demonstrated binding of nuclear Sp1 to these three sites. Sp1-binding activity was also increased in cells treated with TNFa. These studies establish a role for Sp1 in the regulation of expression of the angiogenic factor TP in colon cancer WiDr cells.

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“…The angiogenic factor platelet-derived endothelial cell growth factor is identical to human thymidine phosphorylase (TP), an enzyme that catalyzes the reversible conversion of thymidine to thymine and 2-deoxyribose-1-phosphate; the latter is subsequently converted to 2-deoxyribose (2dR) (15)(16)(17)(18). TP is chemotactic for endothelial cells and has angiogenic activity in several in vivo assays, although it did not directly stimulate endothelial cell proliferation (16 -20).…”

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confidence: 99%

Thymidine Phosphorylase and 2-Deoxyribose Stimulate Human Endothelial Cell Migration by Specific Activation of the Integrins α5β1 and αVβ3

Hotchkiss

Ashton

Schwartz

2003

Journal of Biological Chemistry

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Thymidine phosphorylase is an angiogenic factor that is frequently overexpressed in solid tumors, in rheumatoid arthritis, and in response to inflammatory cytokines. Our previous studies showed that cells expressing thymidine phosphorylase stimulated endothelial cell migration in vitro. This was a consequence of the intracellular metabolism of thymidine by thymidine phosphorylase and subsequent extracellular release of 2-deoxyribose. The mechanisms by which 2-deoxyribose might mediate thymidine phosphorylase-induced cell migration in vitro, however, are obscure. Here we show that both thymidine phosphorylase and 2-deoxyribose stimulated the formation of focal adhesions and the tyrosine 397 phosphorylation of focal adhesion kinase in human umbilical vein endothelial cells. Although similar actions occurred upon treatment with the angiogenic factor vascular endothelial growth factor (VEGF), thymidine phosphorylase differed from VEGF in that its effect on endothelial cell migration was blocked by antibodies to either integrin ␣ 5 ␤ 1 or ␣ v ␤ 3 , whereas VEGFinduced endothelial cell migration was only blocked by the ␣ v ␤ 3 antibody. Further, thymidine phosphorylase and 2-deoxyribose, but not VEGF, increased the association of both focal adhesion kinase and the focal adhesion-associated protein vinculin with integrin ␣ 5 ␤ 1 and, in intact cells, increased the co-localization of focal adhesion kinase with ␣ 5 ␤ 1 . Thymidine phosphorylase and 2-deoxyribose-induced focal adhesion kinase phosphorylation was blocked by the antibodies to ␣ 5 ␤ 1 and ␣ v ␤ 3 , directly linking the migration and signaling components of thymidine phosphorylase and 2-deoxyribose action. Cell surface expression of ␣ 5 ␤ 1 was also increased by thymidine phosphorylase and 2-deoxyribose. These experiments are the first to demonstrate a direct effect of thymidine phosphorylase and 2-deoxyribose on signaling pathways associated with endothelial cell migration.

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Thymidine Phosphorylase Activity Associated with Platelet-Derived Endothelial Cell Growth Factor1

Cited by 121 publications

References 0 publications

Mechanism of trifluorothymidine potentiation of oxaliplatin-induced cytotoxicity to colorectal cancer cells

Mechanism of trifluorothymidine potentiation of oxaliplatin-induced cytotoxicity to colorectal cancer cells

The Sp1 transcription factor contributes to the tumor necrosis factor-induced expression of the angiogenic factor thymidine phosphorylase in human colon carcinoma cells

Thymidine Phosphorylase and 2-Deoxyribose Stimulate Human Endothelial Cell Migration by Specific Activation of the Integrins α5β1 and αVβ3

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