Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin
Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin
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DOI：
10.1200/jco.1997.15.10.3223
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发表时间：
1997-10-01
影响因子：
45.3
通讯作者：
Danenberg, PV
中科院分区：
文献类型：
--
作者：
Leichman, CG;Lenz, HJ;Danenberg, PV
目的：以氟尿嘧啶(5-FU)为基础的治疗有效率仍然很低。随着新的活性药物的测试，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计划治疗。肿瘤内胸苷合成酶(TS)的定量可能是对5-FU敏感或耐药的最重要的决定因素之一。材料和方法：46例播散性结直肠癌患者进行了可测量的肿瘤活检，以聚合酶链式反应(PCR)为基础检测TS mRNA的预处理。5-FU 200 mg/m(2)/d，连用21d，每周静脉滴注亚叶酸钙20 mg/m(2)，2个周期后评价疗效。结果：42例患者(91%)获得了TS/β-肌动蛋白的比值。TS/β-肌动蛋白比值范围为0.3x10(-3)至x18.2 x10(-3)(中位数为3.5x10(-3))。12名患者(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-肌动蛋白比值中值为5.6×10(-3))。TS信使核糖核酸水平大于4.1×10(-3)的患者均无反应。TS/β-肌动蛋白比值的中位数(3.5×10(-3))显著区分了应答者和无应答者(P=.001)。TS/β-肌动蛋白比值小于或等于3.5×10~(-3)的患者的中位生存期为13.6个月；TS/β-肌动蛋白比值大于3.5×10~(-3)的患者的中位生存期为8.2个月(P=0.02)。其他5-FU方案的这种关系尚不清楚。在更大的患者群体中证实这些数据可能导致基于特定的肿瘤内分子参数确定播散性结直肠癌的治疗。(C)1997年，由美国临床肿瘤学会主办。
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/m(2)/d for 21 days with weekly intravenous leucovorin 20 mg/m(2) 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 x 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 less than or equal to 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. (C) 1997 by American Society of Clinical Oncology.