Lenz H J, Hayashi K, Salonga D, Danenberg K D, Danenberg P V, Metzger R, Banerjee D, Bertino J R, Groshen S, Leichman L P, Leichman C G
University of Southern California/Norris Comprehensive Cancer Center, University of Southern California School of Medicine, Los Angeles 90033, USA.
Clin Cancer Res. 1998 May;4(5):1243-50.
Recent studies suggest that there may be a strong correlation between the p53 status of a tumor and a patient's response to chemotherapy. Therefore, we determined p53 status in 36 patients with disseminated colorectal cancer by cDNA sequencing and immunohistochemical staining, as well as by the gene expression level of thymidylate synthase (TS), the target enzyme of 5-fluorouracil (5-FU), by reverse transcription-PCR. Ten patients (28%) experienced a clinical response to 5-FU chemotherapy. Overall, TS expression and response to chemotherapy were associated: 9 of 18 (50%) patients with TS < or = 3.0 x 10(-3) responded, compared to 1 of 18 (6%) patients with TS > 3.0 x 10(-3) (P = 0.003). p53 mutations were found in 21 of 36 patients (58%) using cDNA cycle sequencing, and p53 protein overexpression was found in 20 of 32 patients (62%) using immunohistochemistry staining. Overall p53 status and response to chemotherapy were associated: 5 of 10 (50%) patients with wild-type p53 or negative p53 staining experienced a response, but only 5 of 26 (19%) patients with mutant p53 or p53 overexpression responded. TS expression, but not expression of p53, was significantly associated with overall survival (P = 0.002). Patients with wild-type p53 had significantly lower TS levels compared to patients with mutated p53 (P = 0.044). In this study, we also present data linking specific p53 point mutations to TS expression levels and resistance to 5-FU. Although the number of patients is relatively small, these results identify p53 status and TS gene expression as associated with response in disseminated colorectal cancer; independent studies are needed to confirm these findings and to provide information leading to a better understanding of the role of 5-FU-based chemotherapy in the treatment of colorectal cancer.
近期研究表明，肿瘤的p53状态与患者对化疗的反应之间可能存在密切关联。因此，我们通过cDNA测序和免疫组织化学染色，以及逆转录聚合酶链反应检测胸苷酸合成酶（TS）（5-氟尿嘧啶（5-FU）的靶酶）的基因表达水平，来确定36例播散性结直肠癌患者的p53状态。10例患者（28%）对5-FU化疗有临床反应。总体而言，TS表达与化疗反应相关：TS≤3.0×10⁻³的18例患者中有9例（50%）有反应，而TS＞3.0×10⁻³的18例患者中只有1例（6%）有反应（P = 0.003）。使用cDNA循环测序在36例患者中有21例（58%）发现p53突变，使用免疫组织化学染色在32例患者中有20例（62%）发现p53蛋白过表达。总体p53状态与化疗反应相关：10例野生型p53或p53染色阴性的患者中有5例（50%）有反应，但26例p5３突变或p53过表达的患者中只有5例（19%）有反应。TS表达而非p53表达与总生存期显著相关（P = 0.002）。野生型p53患者的TS水平显著低于p53突变患者（P = 0.044）。在本研究中，我们还提供了将特定p53点突变与TS表达水平及对5-FU耐药性相关联的数据。尽管患者数量相对较少，但这些结果表明p53状态和TS基因表达与播散性结直肠癌的反应相关；需要独立研究来证实这些发现，并提供有助于更好理解基于5-FU的化疗在结直肠癌治疗中作用的信息。
