Salonga D, Danenberg K D, Johnson M, Metzger R, Groshen S, Tsao-Wei D D, Lenz H J, Leichman C G, Leichman L, Diasio R B, Danenberg P V
University of Southern California/Norris Comprehensive Cancer Center, University of Southern California School of Medicine, Los Angeles 90033, USA.
Clin Cancer Res. 2000 Apr;6(4):1322-7.
We had previously shown that high gene expressions (mRNA levels) of thymidylate synthase (TS; Leichman et al., J. Clin. Oncol., 15: 3223-3229, 1997) and thymidine phosphorylase (TP; Metzger et al., Clin. Cancer Res., 4: 2371-2376, 1998) in pretreatment tumor biopsies could identify tumors that would be nonresponsive to 5-fluorouracil (5-FU)-based therapy. In this study, we investigated the association between intratumoral gene expression of the pyrimidine catabolism enzyme dihydropyrimidine dehydrogenase (DPD) and the response of colorectal tumors to the same 5-FU-based protocol. DPD expressions were measured by quantitative reverse transcription-PCR in 33 pretreatment biopsies of colorectal tumors from patients who went on to receive treatment with 5-FU and leucovorin (LV). The range of DPD gene expression in those tumors that were nonresponsive to 5-FU was much broader than that of the responding tumors. None of the tumors with basal-level DPD expressions above a DPD:beta-actin ratio of 2.5 x 10(-3) (14 of 33) were responders to 5-FU/LV therapy, whereas those tumors with DPD gene expressions below DPD: beta-actin ratio of 2.5 x 10(-3) had a response rate of 50%. There was no correlation among DPD, TS, and TP expression values in this set of colorectal tumors, which indicated that these gene expressions are independent variables. All of the tumors that responded to 5-FU therapy (11 of 33) had expression values of all three of the genes, TS, TP, and DPD, below their respective nonresponse cutoff values, whereas, in each of the nonresponding tumors, at least one of these gene expressions was high. The patients with low expression of all three of the genes had significantly longer survival than patients with a high value of any one of the gene expressions. The results of this study show that intratumoral gene expression level of DPD is associated with tumor response to 5-FU and that the use of more than one independent determinant of response permits the identification of a high percentage of responding patients.
我们之前已经表明，在预处理肿瘤活检中胸苷酸合成酶（TS；Leichman等人，《临床肿瘤学杂志》，15: 3223 - 3229, 1997）和胸苷磷酸化酶（TP；Metzger等人，《临床癌症研究》，4: 2371 - 2376, 1998）的高基因表达（mRNA水平）可以识别出对基于5 - 氟尿嘧啶（5 - FU）的治疗无反应的肿瘤。在本研究中，我们调查了嘧啶分解代谢酶二氢嘧啶脱氢酶（DPD）的肿瘤内基因表达与结直肠肿瘤对相同基于5 - FU方案的反应之间的关联。通过定量逆转录 - PCR在33例接受5 - FU和亚叶酸（LV）治疗的患者的结直肠肿瘤预处理活检中测量DPD表达。对5 - FU无反应的肿瘤中DPD基因表达范围比有反应的肿瘤宽得多。DPD基础水平表达高于DPD:β - 肌动蛋白比值2.5×10(-3)的肿瘤（33例中的14例）对5 - FU/LV治疗均无反应，而DPD基因表达低于DPD:β - 肌动蛋白比值2.5×10(-3)的肿瘤反应率为50%。在这组结直肠肿瘤中，DPD、TS和TP表达值之间无相关性，这表明这些基因表达是独立变量。所有对5 - FU治疗有反应的肿瘤（33例中的11例）中，TS、TP和DPD这三个基因的表达值均低于各自的无反应临界值，而在每个无反应的肿瘤中，这些基因表达中至少有一个较高。所有三个基因低表达的患者比任何一个基因高表达的患者生存期显著更长。本研究结果表明，肿瘤内DPD基因表达水平与肿瘤对5 - FU的反应相关，并且使用多个独立的反应决定因素能够识别出高比例的有反应患者。
