Expression of the thymidine phosphorylase gene in epithelial ovarian cancer

Hata, Kohkichi; Kamikawa, Tadao; Arao, Shinji; Tashiro, Hironori; Katabuchi, H.; Okamura, Hitoshi; Fujiwaki, Ritsuto; Miyazaki, Kohji; Fukumoto, Manabu

doi:10.1038/sj.bjc.6690294

Cited by 26 publications

(23 citation statements)

References 31 publications

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“…In experimental models, TP overexpression increased tumour cell invasion (Ueda et al, 2001) and tumorigenicity (Griffiths and Stratford 1998;Brown et al, 2005). In man, high tumour expression of TP generally correlates with a poor prognosis in various solid malignancies (Takebayashi et al, 1996;Ikeda et al, 1999) including cervix cancer (Fujimoto et al, 1999;Hata et al, 1999;Ueda et al, 1999). However, this finding is not universal, as one study in cervix cancer showed that high tumour TP positivity was associated with a good prognosis (Oka et al, 2003).…”

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confidence: 63%

No relationship between thymidine phosphorylase (TP, PD-ECGF) expression and hypoxia in carcinoma of the cervix

et al. 2005

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The expression of hypoxia-regulated genes promotes an aggressive tumour phenotype and is associated with an adverse cancer treatment outcome. Thymidine phosphorylase (TP) levels increase under hypoxia, but the protein has not been studied in association with hypoxia in human tumours. An investigation was made, therefore, of the relationship of tumour TP with hypoxia, the expression of other hypoxia-associated markers and clinical outcome. This retrospective study was carried out in patients with locally advanced cervical carcinoma who underwent radiotherapy. Protein expression was evaluated with immunohistochemistry. Hypoxia was measured using microelectrodes and the level of pimonidazole binding. There was no relationship of TP expression with tumour pO 2 (r ¼ À0.091, P ¼ 0.59, n ¼ 87) or pimonidazole binding (r ¼ 0.13, P ¼ 0.45, n ¼ 38). There was no relationship between TP and HIF1a, but there was a weak borderline significant relationship with HIF-2a expression. There were weak but significant correlations of TP with the expression of VEGF, CA IX and Glut-1. In 119 patients, the presence of TP expression predicted for disease-specific (P ¼ 0.032) and metastasis-free (P ¼ 0.050) survival. The results suggest that TP is not a surrogate marker of hypoxia, but is linked to the expression of hypoxia-associated genes and has weak prognostic power.

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confidence: 63%

No relationship between thymidine phosphorylase (TP, PD-ECGF) expression and hypoxia in carcinoma of the cervix

et al. 2005

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“…24,26 The relative risk of cancer death from tumors with high expression of the TK1, TS and TP genes was greater than the risk from tumors with high expression of any of these genes alone. Although expression of each of these genes alone was not an independent prognostic factor by multivariate analysis, the combined gene expression status of these 3 enzymes was an independent predictor of survival.…”

Section: Relationship Between Expression Of the Tk1 Ts And Tp Genes mentioning

confidence: 99%

“…23,24,26 Levels of TS, TP and DPD gene expression were reported in most patients with malignant ovarian tumors and normal ovaries.…”

Section: Conventional Rt-pcr For Tk1 Gene Expressionmentioning

confidence: 99%

“…26 Briefly, cDNA was prepared by random priming from 500 ng of total RNA using the First-Strand cDNA Synthesis kit (Pharmacia-LKB, Uppsala, Sweden). Pairs of oligonucleotide primers for PCR were designed to insert an intron in the corresponding genomic sequence, to eliminate amplification from genomic DNA.…”

Section: Conventional Rt-pcr For Tk1 Gene Expressionmentioning

confidence: 99%

“…25 The FIGO staging system assumes that an adequate staging operation has been performed and was described elsewhere. 26 Tumors were classified histologically according to the WHO criteria. 27 All patients with epithelial ovarian cancer received cisplatin-based chemotherapy as an adjuvant treatment and were followed to evaluate survival.…”

Section: Patientsmentioning

confidence: 99%

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Thymidine kinase in epithelial ovarian cancer: Relationship with the other pyrimidine pathway enzymes

Fujiwaki

Hata

Nakayama

et al. 2002

Intl Journal of Cancer

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TK is a pyrimidine metabolic pathway enzyme involved in salvage DNA synthesis. What roles TK may play in epithelial ovarian cancer and the relationships between TK and the other pyrimidine pathway enzymes remain unclear. We examined TK1 gene expression by RT-PCR and related it to gene expression of TS, TP and DPD in 69 samples from epithelial ovarian cancer, 8 low-malignant-potential tumors, 16 benign ovarian tumors and 34 normal ovaries. Additionally, cytosolic and serum TK activities were determined by radioenzymatic assay. TK1 gene expression, the ratio of TK1 to TS gene expression, that of TK1 to TP and that of TK1 to DPD were significantly higher in epithelial ovarian cancer than in normal ovaries. In epithelial ovarian cancer, TK1 gene expression correlated with cytosolic and serum TK activities, Key words: thymidine kinase; thymidylate synthase; thymidine phosphorylase; dihydropyrimidine dehydrogenase; epithelial ovarian cancer; radioenzymatic assay; capecitabine TK is an important pyrimidine metabolic pathway enzyme, which catalyzes the phosphorylation of thymidine to deoxythymidine monophosphate using either exogenous or endogenous metabolic thymidine as a substrate. 1 This salvage pathway is the only one by which thymidine is introduced into DNA synthesis. Two isoforms of the TK gene (TK1 and TK2) have been described. 2,3 In addition, a modification of the sequence for TK1 has been described. 4 TK1, which is located in the cytoplasm, is a cell cycleregulated enzyme. 5 Its activity fluctuates with DNA synthesis, being high in dividing and malignant cells and low in quiescent cells. 6,7 TK2 is considered to be located in the mitochondria; levels of TK2 remain relatively constant throughout the cell cycle. Clinical studies have reported elevated serum TK activity in various human malignancies. 8 The majority of these studies concerned hematologic malignancies, but serum TK activity was also elevated in patients with epithelial ovarian cancer. 9 Additionally, serum and cytosolic TK activities appear to have prognostic value in some solid tumors, such as breast, 7,10,11 small cell lung, 12 prostate 13 and cervical 14 cancers. However, little is known about the clinical and prognostic value of tissue TK gene expression in human cancers.TS, TP, DPD and TK are pyrimidine pathway enzymes for de novo DNA synthesis or salvage nucleotide synthesis. TS is an enzyme for the de novo synthesis of deoxythymidine monophosphate (the same product as TK) and is associated with cell proliferative activity. 15,16 TP catalyzes the reversible phosphorolysis of thymidine (the same substrate as TK) to thymine and 2-deoxy-Dribose-1 phosphate 17 and has angiogenic and antiapoptotic effects. 18,19 Subsequently, thymine is degraded to dihydrothymine by DPD, which is inversely related to malignant behavior. 20,21 These 3 enzymes are also responsible for the efficacy and metabolism of fluoropyrimidine cytostatic agents. TS is a critical target enzyme of these drugs. 15 The new agent capecitabine (N 4 -pentyloxycarbonyl-5Ј-deoxy-5-fluo...

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Thymidine phosphorylase and dihydropyrimidine dehydrogenase protein expression in colorectal cancer

et al. 2001

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It is essential for actively proliferating cells to increase their rate of DNA synthesis to progress through the cell cycle. This is reflected in the increased uracil usage that is a common feature in solid tumours. Thymidine phosphorylase (TP) anabolises formation of pyrimidine nucleosides available for DNA synthesis, whereas dihydropyrimidine dehydrogenase (DPD) catabolises the degradation of pyrimidine bases, thereby reducing levels of uracil and thymine available for DNA synthesis. In addition, tissue levels of TP or DPD have been associated with the clinical efficacy of pyrimidine antimetabolites commonly used in the treatment of colorectal cancer. There is little information, however, on the relative expression or degree of co-ordinated regulation of either protein in primary or metastatic colorectal cancer. DPD and TP protein levels were measured in 15 primary colorectal carcinomas, 10 colorectal liver metastases and 25 adjacent uninvolved tissues. DPD was reduced in 67% ( Key words: thymidine phosphorylase; dihydropyrimidine dehydrogenase; colorectal cancerColorectal cancer has world-wide health implications, with around 0.5 million people still succumbing to the disease each year. Approximately 60% of patients present with metastatic disease and because almost all die of the disease, current therapies are clearly inadequate. 5-Fluorouracil (5FU) is 1 of the most frequently prescribed chemotherapy medications with single agent activity against colorectal cancer. 1 5-FU is also an active component of combination chemotherapy for breast, lung and stomach cancer. Although 5-FU has been in clinical use since the 1950s, recently more effective 5FU-based treatment regimens have been developed, which use prolonged continuous infusion or combination therapy with modulators such as leucovorin. 2 Objective tumour responses have been observed with infusional 5-FU in patients unresponsive or resistant to bolus 5-FU. Continuous intravenous infusion is expensive, however, and associated with significant morbidity. This has led to the development of new oral fluoropyrimidines, such as capecitabine, S-1 and UFT. [3][4][5] Thymidine phosphorylase (TP) catalyses enhanced tumour-specific activation of fluoropyrimidines to 5-FU and 5-FdUrd, which are then further metabolised to cytotoxic fluoro-nucleotides. 3,5 In contrast, 5-FU is catabolised to relatively inactive products by dihydropyrimidine dehydrogenase (DPD). 3,5 The importance of these enzymes systems has recently been highlighted in a study of 24 human xenografts. 6 Although a high degree of variability in both TP and DPD activity was observed in the tumour xenografts, the efficacy of capecitabine and doxifluridine appeared to be regulated by the TP:DPD ratio in the tumour tissue. 6 A similar conclusion can be drawn from clinical studies of capecitabine in colorectal cancer patients, where activation to 5FU was enhanced in tumour tissue. 7 The enhanced capecitabine activation was mainly attributed to increased TP activity in the tumour tissues. 7 A number of diffe...

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Expression of the thymidine phosphorylase gene in epithelial ovarian cancer

Cited by 26 publications

References 31 publications

No relationship between thymidine phosphorylase (TP, PD-ECGF) expression and hypoxia in carcinoma of the cervix

No relationship between thymidine phosphorylase (TP, PD-ECGF) expression and hypoxia in carcinoma of the cervix

Thymidine kinase in epithelial ovarian cancer: Relationship with the other pyrimidine pathway enzymes

Thymidine phosphorylase and dihydropyrimidine dehydrogenase protein expression in colorectal cancer

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