Clinical significance of thymidylate synthase expression in bladder cancer.
BACKGROUND
The purpose of the present paper was to investigate the clinical significance of thymidylate synthase (TS) expression in bladder cancer and its association with proliferation markers, such as p53, Ki-67, and proliferating cell nuclear antigen (PCNA).


METHODS
Thymidylate synthase gene expression in 54 patients with bladder cancer was measured by the reverse transcription polymerase chain reaction (RT-PCR) method using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as an internal standard. The TS expression was also examined immunohistochemically. Immunohistochemical studies of p53, Ki-67, and PCNA expression were carried out to examine the correlation between TS expression and the expression of proliferation markers in the tumors. Prognostic and clinical outcome factors such as vascular invasion and distant metastasis were also examined along with TS expression.


RESULTS
Twenty-four patients with invasive bladder cancer had TS levels of 5.07 +/- 0.77 (mean +/- SE), while 30 patients with superficial bladder cancer had TS levels of 2.28 +/- 0.38. There was a significant difference in TS levels between invasive and superficial bladder cancer (P = 0.001). There was a positive correlation between TS expression and each proliferation marker of p53 (r = 0.686, P < 0.01), Ki-67 (r = 0.715, P < 0.0001) or PCNA expressions (r = 0.670, P < 0.0001) in these patients. Patients with high TS levels (TS > or = 2.63, the median value) had significantly higher rates of vascular invasion and distant metastasis. Kaplan-Meier analysis demonstrated that patients with high TS levels (TS > or = 2.63) had unfavorable prognosis compared to patients with low TS levels (TS < 2.63; P = 0.034). Furthermore, patients with high TS staining had a significantly poorer prognosis than those with low staining (P = 0.012).


CONCLUSIONS
Determination of level of TS expression may help in the selection of an appropriate treatment for bladder cancer because TS expression influences the biological characteristic of bladder tumor.
Nomura
Takeo
T
Department of Urology, Oita Medical University, Hasamamachi, Oita, Japan. TAKE@oita-med.ac.jp
Nakagawa
Masayuki
M
Fujita
Yoshitsugu
Y
Hanada
Toshikatsu
T
Mimata
Hiromitsu
H
Nomura
Yoshio
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D013940:Thymidylate Synthase / Q000032:analysis*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D001749:Urinary Bladder Neoplasms / Q000737:chemistry / Q000201:enzymology*
D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; D013940:Thymidylate Synthase