Prognostic Role of Thymidylate Synthase, Thymidine Phosphorylase/ Platelet-derived Endothelial Cell Growth Factor, and Proliferation Markers in Colorectal Cancer

• Published in: Clinical cancer research Vol. 6; no. 3; pp. 1063 - 1072
• Main Authors: van Triest, B, Pinedo, H M, Blaauwgeers, J L, van Diest, P J, Schoenmakers, P S, Voorn, D A, Smid, K, Hoekman, K, Hoitsma, H F, Peters, G J
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01-03-2000
• Subjects: Aged; Biomarkers - analysis; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Endothelial Growth Factors - analysis; Female; Humans; Immunohistochemistry; Ki-67 Antigen - analysis; Lymphokines - analysis; Male; Middle Aged; Neovascularization, Pathologic - pathology; Platelet Endothelial Cell Adhesion Molecule-1 - analysis; Prognosis; Survival Analysis; Thymidine Phosphorylase - analysis; Thymidine Phosphorylase - metabolism; Thymidylate Synthase - analysis; Thymidylate Synthase - metabolism; Tumor Suppressor Protein p53 - analysis; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
• ISSN: 1078-0432; 1557-3265

5-Fluorouracil
(5FU)-based therapy is given to patients with advanced colorectal
cancer and as adjuvant treatment. Thymidylate synthase (TS) is the
target for 5FU, and may have a prognostic role for the outcome of
5FU-based therapy together with proliferation markers such as p53 and
Ki67. Thymidine phosphorylase (TP, also known as platelet-derived
endothelial cell growth factor) may be of importance both in the
5FU drug activation pathway and in tumor angiogenesis, similar to
vascular endothelial growth factor (VEGF). TS and TP levels were
determined biochemically in fresh-frozen tumor specimens of 32
untreated patients with colorectal cancer, whereas in paraffin-embedded
tissue samples, immunohistochemistry was performed for TS, TP, and
additional prognostic markers such as p53, Ki67, and VEGF as well as
microvessel density. All factors were correlated with patient
characteristics such as age, gender, Dukes’ stage, angio-invasion, and
differentiation grade. TS and TP as measured by various assays were
correlated with overall and disease-free survival in this patient
group. TP enzyme activity and protein expression correlated with each
other. A significant correlation was found between TP enzyme activity
and 5-fluoro-2′-deoxyuridine-5′-monophosphate binding activity. VEGF
expression correlated significantly with TP immunostaining and Ki67
index. Survival analysis revealed a significant relation of TS levels
to the overall survival in this small patient group and a significant
correlation between TP activity and disease-free survival. TS and TP
both were of prognostic significance in these patients with colorectal
cancer. The interesting relationship of TS and TP with angiogenesis and
proliferation needs further investigation.