Foekens J A, Romain S, Look M P, Martin P M, Klijn J G
Department of Medical Oncology, Rotterdam Cancer Institute, Daniel den Hoed Kliniek, Academic Hospital Rotterdam, The Netherlands.
Cancer Res. 2001 Feb 15;61(4):1421-5.
Thymidylate synthase (TS) is a crucial target for 5-fluorouracil (5-FU) in the de novo pathway of pyrimidine synthesis, which is necessary for DNA synthesis. Thymidine kinase (TK) plays a key role in the complementary or alternative salvage pathway of pyrimidine synthesis in acute or pathological tissue stress. In the present study, the activity levels of TS and TK were determined in 257 primary breast tumors of patients who received tamoxifen as first-line systemic therapy after diagnosis of advanced disease. In 155 (60%) responding patients, the median response duration was 23 months for tumors with low TK activity, 15 months for tumors with intermediate TK activity, and 13 months for tumors with high TK activity (P = 0.003). In Cox multivariate analysis corrected for classical predictive factors including estrogen receptor and progesterone receptor, patients with intermediate and high levels of TK activity in their tumors showed a rapid disease progression (P = 0.0002) and an early death (P = 0.002) after start of tamoxifen treatment. Tumor TS activity levels were not significantly associated with the efficacy of tamoxifen treatment. In 121 patients who became resistant to tamoxifen or additional endocrine treatments and who received 5-FU-containing polychemotherapy, tumor TK activity was not significantly related to the efficacy of chemotherapy. Of the 13 patients with low tumor TS activity, only 1 (8%) responded favorably, whereas 46% (43 of 93) of those with intermediate and 73% (11 of 15) of those with high TS activity responded (P = 0.001). In Cox multivariate regression analysis in which TS was the only significant variable, intermediate and high TS activities were associated with a slow disease progression (P = 0.005) and prolonged survival (P = 0.016) on chemotherapy. In conclusion, for patients with recurrent breast cancer, high tumor TK activity is a significant marker of poor clinical outcome on tamoxifen therapy. Elevated tumor TS activity predicts a favorable outcome for 5-FU-containing polychemotherapy when applied after tumor progression on endocrine therapy.
胸苷酸合成酶（TS）是嘧啶合成从头途径中5-氟尿嘧啶（5-FU）的关键靶点，而嘧啶合成是DNA合成所必需的。胸苷激酶（TK）在急性或病理性组织应激时嘧啶合成的互补或替代补救途径中起关键作用。在本研究中，测定了257例晚期疾病诊断后接受他莫昔芬作为一线全身治疗的患者原发性乳腺肿瘤中TS和TK的活性水平。在155例（60%）有反应的患者中，TK活性低的肿瘤患者中位反应持续时间为23个月，TK活性中等的肿瘤患者为15个月，TK活性高的肿瘤患者为13个月（P = 0.003）。在对包括雌激素受体和孕激素受体等经典预测因素进行校正的Cox多变量分析中，肿瘤TK活性中等和高的患者在开始他莫昔芬治疗后疾病进展迅速（P = 0.0002）且早期死亡（P = 0.002）。肿瘤TS活性水平与他莫昔芬治疗的疗效无显著相关性。在121例对他莫昔芬或其他内分泌治疗耐药并接受含5-FU多药化疗的患者中，肿瘤TK活性与化疗疗效无显著相关性。在13例肿瘤TS活性低的患者中，只有1例（8%）反应良好，而TS活性中等的患者中有46%（93例中的43例）和TS活性高的患者中有73%（15例中的11例）有反应（P = 0.001）。在以TS为唯一显著变量的Cox多变量回归分析中，TS活性中等和高与化疗时疾病进展缓慢（P = 0.005）和生存期延长（P = 0.016）相关。总之，对于复发性乳腺癌患者，肿瘤TK活性高是他莫昔芬治疗临床预后不良的重要标志物。内分泌治疗后肿瘤进展时应用含5-FU多药化疗，肿瘤TS活性升高预示着良好的预后。
