RESPONSE TO FLUOROURACIL THERAPY IN CANCER-PATIENTS - THE ROLE OF TUMORAL DIHYDROPYRIMIDINE DEHYDROGENASE-ACTIVITY
RESPONSE TO FLUOROURACIL THERAPY IN CANCER-PATIENTS - THE ROLE OF TUMORAL DIHYDROPYRIMIDINE DEHYDROGENASE-ACTIVITY
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DOI：
10.1200/jco.1995.13.7.1663
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发表时间：
1995-07-01
影响因子：
45.3
通讯作者：
MILANO, G
中科院分区：
文献类型：
--
作者：
ETIENNE, MC;CHERADAME, S;MILANO, G
目的：本研究的目的是分析胸苷酸合成酶（TS的主要细胞靶氟尿嘧啶[FU]）和二氢嘧啶脱氢酶（DPD; FU catalysts的限速酶）在肿瘤活检的作用与FU responsibility.Patients和方法：这项前瞻性研究进行了62头颈部癌症患者（6个阶段II，16个阶段III，和40个阶段IV）。所有患者均接受生物调节FU一线化疗（连续输注5天）。治疗前，获得肿瘤活检和对照活检（对称的非肿瘤区域）。胞质TS和DPD活动测定使用radioenzymatic assays.Results：DPD活性是可检测的所有样品中，肿瘤（中位数，60 pmol/min/mg蛋白质;范围，13至193）和非肿瘤样品（中位数，68 pmol/min/mg蛋白质;范围，12至150）之间没有显着差异。肿瘤TS和肿瘤DPD不受肿瘤定位或肿瘤分期的显著影响。在52例可评估临床反应的肿瘤中，我们观察到46%的完全反应（CR），33%的部分反应（PR）和21%的无反应（NR）。TS活性和对FU治疗的反应之间没有关系。完全应答者和部分或无应答者之间肿瘤DPD的比较显示出显著性趋势（P = .06）。为了减少变异性，我们分析了肿瘤/非肿瘤DPD活性比;完全应答者的标准化DPD显著低于部分或无应答患者（CR、PR和NR的中位数分别为0.86、1.18和1.42; CR vs PR + NR，P = 0.03）。虽然对FU的耐药性是多因素的，但目前的临床研究表明，靶细胞中的FU催化可能是癌症患者FU反应性的决定性因素，并证明了特异性DPD抑制剂作为FU生物调节剂的临床使用是合理的。
Purpose: The aim of the present study was to analyze the role of thymidylate synthase (TS; main cellular target of fluorouracil [FU]) and dihydropyrimidine dehydrogenase (DPD; rate-limiting enzyme of FU catabolism) in tumoral biopsies with respect to FU responsiveness.Patients and Methods: This prospective study was conducted on 62 head and neck cancer patients (six stage II, 16 stage III, and 40 stage IV). All received first-line chemotherapy with biomodulated FU (5-day continuous infusion). Before treatment, a tumor biopsy and control biopsy (symmetrical nontumoral area) were obtained. Cytosolic TS and DPD activities were measured using radioenzymatic assays.Results: DPD activity was detectable in all samples, without a significant difference between tumoral (median, 60 pmol/min/mg protein; range, 13 to 193) and nontumoral samples (median, 68 pmol/min/mg protein; range, 12 to 150). Tumoral TS and tumoral DPD were not significantly influenced by tumor localization or tumor staging. Among 52 tumors assessable for clinical response, we observed 46% complete responses (CRs), 33% partial responses (PRs), and 21% no responses (NRs). No relationship was demonstrated between TS activity and response to FU therapy. The comparison of tumoral DPD between complete responders and partial or nonresponders showed a trend toward significance (P = .06). In an attempt to reduce variability, we analyzed the tumoral/nontumoral DPD activity ratio; complete responders exhibited a significantly lower normalized DPD than partial or nonresponding patients (median, 0.86, 1.18, and 1.42 for CR, PR, and NR, respectively; CR v PR plus NR, P = .03).Conclusion: Although resistance to FU is multifactorial, the present clinical study suggests that FU catabolism in target cells is probably a determinant factor for FU responsiveness in cancer patients and justifies the clinical use of specific DPD inhibitors as FU biomodulators.