Can Thymidine Kinase Levels in Breast Tumors Predict Disease Recurrence?

O’Neill, Kim L.; Hoper, Margaret; Odling-Smee, G. W.

doi:10.1093/jnci/84.23.1825

Cited by 38 publications

(25 citation statements)

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“…14,30 The kit used here for TK measurement is optimized for the fetal cytosolic TK1 isoenzyme. In experimental models, TK1 expression also has been strongly associated with S-phase: 31 TK1 increases markedly after the G1-S transition 8,12 and a high affinity TK1 tetramer is specifically found in S-phase cells. 32,33 Although TS activity has been associated with proliferation, it has not been closely linked with S-phase.…”

Section: Multivariate Prognostic Analysesmentioning

confidence: 99%

“…8,12 High TK values have been correlated with poor survival, 8,[13][14][15][16] especially in node-negative patients receiving no systemic adjuvant therapy. 13,16 However, the relative importance of TK and other quantitative measures of proliferation is currently unknown.…”

mentioning

confidence: 99%

“…The de novo pathway is predominant in normal differentiated tissues, whereas the salvage pathway is activated in rapidly proliferating tissues, including fetal and regenerative tissues and human breast cancers. 8,9 Enzyme inactivators of de novo synthesis are effective adjuvant agents in the treatment of breast tumors. 10 In contrast, only weak inhibitors of the salvage pathway have been described 11 and they cannot be used in cancer treatment.…”

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confidence: 99%

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DNA-synthesizing enzymes in breast cancer (thymidine kinase, thymidylate synthase and thymidylate kinase): Association with flow cytometric s-phase fraction and relative prognostic importance in node-negative premenopausal patients

et al. 2001

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Section: Multivariate Prognostic Analysesmentioning

confidence: 99%

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confidence: 99%

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DNA-synthesizing enzymes in breast cancer (thymidine kinase, thymidylate synthase and thymidylate kinase): Association with flow cytometric s-phase fraction and relative prognostic importance in node-negative premenopausal patients

et al. 2001

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“…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.…”

mentioning

confidence: 99%

“…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.…”

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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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DNA-synthesis enzyme activity: A biological tool useful for predicting anti-metabolic drug sensitivity in breast cancer?

et al. 1997

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Thymidine kinase (TK) and thymidylate synthase (TS) play a key role in, respectively, the salvage and the de novo DNA synthesis pathways. TS is a crucial target for 5-fluorouracil(5-FU) and may also influence methotrexate(MTX) efficiency. Tyrosine kinase(TPK) has been associated with the cytoplasmic domain of growth factor receptors as well as oncoproteins. We investigated whether TK, TS and TPK are predictive factors for drug sensitivity evaluated in terms of relapse-free improvement in breast-cancer patients receiving adjuvant chemotherapy. TK, TS and TPK activities were determined in the cytosols of 154 node-positive primary breast cancers. All patients received 5-FU containing adjuvant chemotherapy. Measurements were performed using radioenzymatic methods. The levels of TK were correlated with those of TS and TPK. The levels of TS and TPK were less strongly correlated with each other. High TK levels were more often found in larger tumours, and the levels of both TK and TPK were negatively correlated with those of PgR. Patients whose tumours contained high levels of TK had increased risks of relapse and death. TS was not of prognostic value, while a high level of TPK was associated with early death. In Cox analysis, TK and TPK retained their independent prognostic value. While target enzyme activities on the de novo DNA synthesis pathway could determine response to anti-metabolics mainly inhibiting this pathway, high activities on the alternative salvage pathway could circumvent induced growth inhibition. Int. J. Cancer 74:156-161, 1997.r 1997 Wiley-Liss, Inc.Systemic adjuvant chemotherapy reduces the risk of relapse and death in breast-cancer patients. At present, however, the impact of adjuvant chemotherapy in overall populations is relatively modest. Factors that predict response to therapy rather than prognosis alone may thus be important to more precisely guide the individualized selection of appropriate treatment. Improvement of therapeutic score of specific protocols may be obtained by selecting only responder patients and moving unselected patients into innovating protocols.High growth fraction is an established adverse prognostic factor in the natural history of breast cancer. Until now, growth fraction has been mainly derived from mitotic index (Clayton, 1991), thymidine labeling index (Silvestrini et al., 1986) and DNA flow cytometry (Clark et al., 1989). These parameters do not discriminate between the 2 alternative pathways of salvage and de novo DNA synthesis. The adjuvant chemotherapy most widely used in European countries is the combination of cyclophosphamide, methotrexate and 5-fluorouracil (CMF), and in most studies the overall indicators of disturbed proliferation remain highly significant. On the basis of theoretical aspects, of results obtained in experimental models and of clinical evidence, cytotoxic agents should act specifically against actively proliferating cells. These data therefore strongly suggest that response to treatment is not uniform in rapidly proliferating tumours when d...

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Can Thymidine Kinase Levels in Breast Tumors Predict Disease Recurrence?

Cited by 38 publications

References 0 publications

DNA-synthesizing enzymes in breast cancer (thymidine kinase, thymidylate synthase and thymidylate kinase): Association with flow cytometric s-phase fraction and relative prognostic importance in node-negative premenopausal patients

DNA-synthesizing enzymes in breast cancer (thymidine kinase, thymidylate synthase and thymidylate kinase): Association with flow cytometric s-phase fraction and relative prognostic importance in node-negative premenopausal patients

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

DNA-synthesis enzyme activity: A biological tool useful for predicting anti-metabolic drug sensitivity in breast cancer?

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