肿瘤内胸苷酸合成酶表达的定量分析可预测播散性结直肠癌对持续输注氟尿嘧啶和每周亚叶酸的反应及耐药性。

Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin.

作者信息

Leichman C G, Lenz H J, Leichman L, Danenberg K, Baranda J, Groshen S, Boswell W, Metzger R, Tan M, Danenberg P V

机构信息

Department of Medicine, University of Southern California, Los Angeles, USA.

出版信息

J Clin Oncol. 1997 Oct;15(10):3223-9. doi: 10.1200/JCO.1997.15.10.3223.

DOI:10.1200/JCO.1997.15.10.3223

PMID:9336359

Abstract

PURPOSE

Response rates to fluorouracil (5-FU)-based therapy remain low. As new, active agents are being tested, information regarding specific intratumoral genetic determinants of chemotherapy sensitivity or resistance can be used to plan therapy rationally. Intratumoral thymidylate synthase (TS) quantitation may be among the most important determinants of sensitivity or resistance to 5-FU.

MATERIALS AND METHODS

Forty-six disseminated colorectal cancer patients had measurable tumor biopsies for polymerase chain reaction (PCR)-based determination of TS mRNA pretreatment. Protracted infusion of 5-FU 200 mg/m2/d for 21 days with weekly intravenous leucovorin 20 mg/m2 each cycle was given. After two cycles, responses were evaluated. Response data were correlated with independently determined intratumoral ratios of TS/beta-actin mRNA for each patient.

RESULTS

TS/beta-actin ratios were successfully obtained for 42 patients (91%). TS/beta-actin ratios ranged from 0.3 x 10(-3) to 18.2 x 10(-3) (median, 3.5 x 10[-3]). Twelve patients (26%) responded to treatment (median TS/beta-actin ratio, 1.7 x 10[+3]). Thirty-four patients did not respond (median TS/beta-actin ratio, 5.6 x 10[-3]). No patient with a TS mRNA level greater than 4.1 x 10(-3) responded. The median TS/beta-actin ratio (3.5 x 10[-3]) significantly segregated responders from nonresponders (P = .001). Median survival for patients with TS/beta-actin ratios < or = 3.5 x 10(-3) was 13.6 months; for patients with TS/beta-actin ratios greater than 3.5 x 10(-3), it was 8.2 months (P = .02).

CONCLUSION

For this cohort, the intratumoral TS/beta-actin ratio had a statistically significant association with response and survival. This relationship for other 5-FU schedules remains unknown. Confirmation of these data in a larger patient population could lead to determination of therapy for disseminated colorectal cancer based on a specific intratumoral molecular parameter.

摘要

目的

基于氟尿嘧啶（5-FU）的治疗反应率仍然很低。随着新型活性药物的不断试验，有关化疗敏感性或耐药性的特定肿瘤内基因决定因素的信息可用于合理规划治疗方案。肿瘤内胸苷酸合成酶（TS）定量可能是对5-FU敏感性或耐药性的最重要决定因素之一。

材料与方法

46例播散性结直肠癌患者接受了可测量的肿瘤活检，用于基于聚合酶链反应（PCR）的TS mRNA预处理测定。每个周期持续输注5-FU 200mg/m²/d，共21天，每周静脉注射亚叶酸20mg/m²。两个周期后评估反应情况。将反应数据与每位患者独立测定的肿瘤内TS/β-肌动蛋白mRNA比值进行关联分析。

结果

成功获得了42例患者（91%）的TS/β-肌动蛋白比值。TS/β-肌动蛋白比值范围为0.3×10⁻³至18.2×10⁻³（中位数为3.5×10⁻³）。12例患者（26%）对治疗有反应（TS/β-肌动蛋白比值中位数为1.7×10⁻³）。34例患者无反应（TS/β-肌动蛋白比值中位数为5.6×10⁻³）。TS mRNA水平大于4.1×10⁻³的患者均无反应。TS/β-肌动蛋白比值中位数（3.5×10⁻³）将有反应者与无反应者显著区分开来（P = 0.001）。TS/β-肌动蛋白比值≤3.5×10⁻³的患者中位生存期为13.6个月；TS/β-肌动蛋白比值大于3.5×10⁻³的患者中位生存期为8.2个月（P = 0.02）。