p53 point mutations and thymidylate synthase messenger RNA levels in disseminated colorectal cancer: an analysis of response and survival.
p53 point mutations and thymidylate synthase messenger RNA levels in disseminated colorectal cancer: an analysis of response and survival.
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发表时间：
1998-05
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通讯作者：
H. Lenz;K. Hayashi;D. Salonga;K. Danenberg;P. Danenberg;R. Metzger;D. Banerjee;J. Bertino;S. Groshen;L. Leichman;C. Leichman
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作者：
H. Lenz;K. Hayashi;D. Salonga;K. Danenberg;P. Danenberg;R. Metzger;D. Banerjee;J. Bertino;S. Groshen;L. Leichman;C. Leichman
最近的研究表明，肿瘤的p53状态与患者对化疗的反应之间可能存在很强的相关性。因此，我们确定了p53状态在36例播散性结直肠癌的cDNA测序和免疫组化染色，以及通过基因表达水平的胸苷酸合成酶（TS），5-氟尿嘧啶（5-FU）的靶酶，通过逆转录-PCR。10例患者（28%）对5-FU化疗有临床应答。总体而言，TS表达和对化疗的反应相关：18例患者中有9例（50%）TS 3.0 x 10（-3）（P = 0.003）。用cDNA循环测序法在36例患者中发现21例（58%）p53突变，用免疫组化染色法在32例患者中发现20例（62%）p53蛋白过度表达。总体p53状态和对化疗的反应相关：10例野生型p53或阴性p53染色的患者中有5例（50%）出现反应，但26例突变型p53或p53过表达的患者中只有5例（19%）出现反应。TS表达，而不是p53的表达，与总生存率显著相关（P = 0.002）。与突变型p53患者相比，野生型p53患者的TS水平显着较低（P = 0.044）。在这项研究中，我们还提出了特定的p53点突变的TS表达水平和耐药性的数据。虽然患者数量相对较少，但这些结果确定了p53状态和TS基因表达与播散性结直肠癌的反应相关;需要独立的研究来证实这些发现，并提供信息，以更好地了解基于5-FU的化疗在结直肠癌治疗中的作用。
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 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.