Etienne M C, Chéradame S, Fischel J L, Formento P, Dassonville O, Renée N, Schneider M, Thyss A, Demard F, Milano G
Centre Antoine Lacassagne, Nice, France.
J Clin Oncol. 1995 Jul;13(7):1663-70. doi: 10.1200/JCO.1995.13.7.1663.
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.
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.
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).
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.
本研究旨在分析胸苷酸合成酶（TS；氟尿嘧啶[FU]的主要细胞靶点）和二氢嘧啶脱氢酶（DPD；FU分解代谢的限速酶）在肿瘤活检中对FU反应性的作用。
本前瞻性研究对62例头颈部癌患者（6例II期、16例III期和40例IV期）进行。所有患者均接受一线生物调节FU化疗（5天持续输注）。治疗前，获取肿瘤活检组织和对照活检组织（对称的非肿瘤区域）。使用放射酶法测定胞质TS和DPD活性。
所有样本中均可检测到DPD活性，肿瘤样本（中位数为60 pmol/分钟/毫克蛋白；范围为13至193）与非肿瘤样本（中位数为68 pmol/分钟/毫克蛋白；范围为12至150）之间无显著差异。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%的完全缓解（CR）、33%的部分缓解（PR）和21%的无反应（NR）。未证明TS活性与FU治疗反应之间存在关联。完全缓解者与部分缓解或无反应者之间肿瘤DPD的比较显示出显著趋势（P = 0.06）。为了减少变异性，我们分析了肿瘤/非肿瘤DPD活性比值；完全缓解者的标准化DPD显著低于部分缓解或无反应患者（CR、PR和NR的中位数分别为0.86、1.18和1.42；CR与PR加NR相比，P = 0.03）。
尽管对FU的耐药是多因素的，但本临床研究表明，靶细胞中的FU分解代谢可能是癌症患者对FU反应性的决定因素，并证明了将特定DPD抑制剂作为FU生物调节剂的临床应用合理性。
