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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

Romain, S ; Bendahl, P O LU ; Guirou, O ; Malmström, P LU ; Martin, P M and Fernö, M LU (2001) In International Journal of Cancer 95(1). p.56-61
Abstract

S-phase fraction (SPF) is a reference for cell-kinetic analysis. In this study, the links between SPF and the essential enzymes participating in the pyrimidine synthesis were investigated in breast cancer and their relationships with the natural history of the disease were compared. We measured thymidine kinase (TK) for salvage synthesis, thymidylate synthase (TS) for de novo synthesis and thymidylate kinase (TMK), which is required for both pathways. Our study population consisted of 211 premenopausal women with node-negative tumors. SPF was assessed prospectively by flow cytometry, whereas enzyme activities were measured retrospectively in cytosols using radioenzymatic methods. Among the enzymes analyzed, only TK demonstrated a strong... (More)

S-phase fraction (SPF) is a reference for cell-kinetic analysis. In this study, the links between SPF and the essential enzymes participating in the pyrimidine synthesis were investigated in breast cancer and their relationships with the natural history of the disease were compared. We measured thymidine kinase (TK) for salvage synthesis, thymidylate synthase (TS) for de novo synthesis and thymidylate kinase (TMK), which is required for both pathways. Our study population consisted of 211 premenopausal women with node-negative tumors. SPF was assessed prospectively by flow cytometry, whereas enzyme activities were measured retrospectively in cytosols using radioenzymatic methods. Among the enzymes analyzed, only TK demonstrated a strong correlation with SPF (r(s) = 0.59). In univariate analysis, high SPF and high levels of TK were associated with increased risk of developing distant recurrences (p < 0.001). Correlations with other prognostic factors (histological grade, steroid receptors, DNA ploidy status, urokinase plasminogen activator and plasminogen activator inhibitor type 1) confirmed a parallel association of SPF and TK with the most aggressive tumors. In contrast, TS and TMK were not associated with prognosis. After adjustment for SPF, the risk of relapse increased significantly with TK values. Subgroup analysis showed that additional information was provided by TK in the tumors with low SPF. When urokinase plasminogen activator (uPA) was a candidate variable in multivariate analysis, TK remained significant. Combined with SPF and uPA, TK could be useful to define premenopausal node-negative patients with rapidly proliferating tumors at a high risk of metastatic disease.

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author
; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
Adult, Breast Neoplasms/metabolism, Female, Flow Cytometry, Humans, Kinetics, Lymphatic Metastasis, Middle Aged, Nucleoside-Phosphate Kinase/biosynthesis, Plasminogen Activator Inhibitor 1/biosynthesis, Premenopause, Prognosis, Recurrence, Risk Factors, S Phase, Thymidine Kinase/biosynthesis, Thymidylate Synthase/biosynthesis, Time Factors, Urokinase-Type Plasminogen Activator/biosynthesis
in
International Journal of Cancer
volume
95
issue
1
pages
56 - 61
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:11241312
  • scopus:0035915770
ISSN
0020-7136
DOI
10.1002/1097-0215(20010120)95:1<56::aid-ijc1010>3.0.co;2-3
language
English
LU publication?
no
additional info
Copyright 2001 Wiley-Liss, Inc.
id
a830f788-af0d-4eed-b0fa-cd72ccf3e56f
date added to LUP
2022-03-02 13:28:17
date last changed
2025-01-02 18:38:09
@article{a830f788-af0d-4eed-b0fa-cd72ccf3e56f,
  abstract     = {{<p>S-phase fraction (SPF) is a reference for cell-kinetic analysis. In this study, the links between SPF and the essential enzymes participating in the pyrimidine synthesis were investigated in breast cancer and their relationships with the natural history of the disease were compared. We measured thymidine kinase (TK) for salvage synthesis, thymidylate synthase (TS) for de novo synthesis and thymidylate kinase (TMK), which is required for both pathways. Our study population consisted of 211 premenopausal women with node-negative tumors. SPF was assessed prospectively by flow cytometry, whereas enzyme activities were measured retrospectively in cytosols using radioenzymatic methods. Among the enzymes analyzed, only TK demonstrated a strong correlation with SPF (r(s) = 0.59). In univariate analysis, high SPF and high levels of TK were associated with increased risk of developing distant recurrences (p &lt; 0.001). Correlations with other prognostic factors (histological grade, steroid receptors, DNA ploidy status, urokinase plasminogen activator and plasminogen activator inhibitor type 1) confirmed a parallel association of SPF and TK with the most aggressive tumors. In contrast, TS and TMK were not associated with prognosis. After adjustment for SPF, the risk of relapse increased significantly with TK values. Subgroup analysis showed that additional information was provided by TK in the tumors with low SPF. When urokinase plasminogen activator (uPA) was a candidate variable in multivariate analysis, TK remained significant. Combined with SPF and uPA, TK could be useful to define premenopausal node-negative patients with rapidly proliferating tumors at a high risk of metastatic disease.</p>}},
  author       = {{Romain, S and Bendahl, P O and Guirou, O and Malmström, P and Martin, P M and Fernö, M}},
  issn         = {{0020-7136}},
  keywords     = {{Adult; Breast Neoplasms/metabolism; Female; Flow Cytometry; Humans; Kinetics; Lymphatic Metastasis; Middle Aged; Nucleoside-Phosphate Kinase/biosynthesis; Plasminogen Activator Inhibitor 1/biosynthesis; Premenopause; Prognosis; Recurrence; Risk Factors; S Phase; Thymidine Kinase/biosynthesis; Thymidylate Synthase/biosynthesis; Time Factors; Urokinase-Type Plasminogen Activator/biosynthesis}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{56--61}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{International Journal of Cancer}},
  title        = {{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}},
  url          = {{http://dx.doi.org/10.1002/1097-0215(20010120)95:1<56::aid-ijc1010>3.0.co;2-3}},
  doi          = {{10.1002/1097-0215(20010120)95:1<56::aid-ijc1010>3.0.co;2-3}},
  volume       = {{95}},
  year         = {{2001}},
}