Combined evaluation of dihydropyrimidine dehydrogenase and thymidine phosphorylate mRNA levels in tumor predicts the histopathological effect of 5-fluorouracil-based chemoradiotherapy

Weng

J. Huazhong Univ. Sci. Technol. [Med. Sci.]

et al. 2010

The mRNA and protein expression of thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) and their relationship with prognosis were investigated. Real-time quantitative RT-PCR (Taqman) was used to detect the mRNA expression of TS, TP and DPD in formalin-fixed and paraffin-embedded 106 samples of epithelial ovarian cancer and 29 normal ovaries. A TATA box-binding protein (TBP) was used as an endogenous reference gene. A relationship between TS, TP, DPD expression and clinicopathologic features was investigated. The protein location and expression of TS, TP and DPD was examined in the same patients by an avidin-biotin-peroxidase immunohistochemistry. TS and TP mRNA expression levels were significantly higher in tumor group than in normal controls, with the average value of TS and TP mRNA being 6.14+/-0.62 and 0.59+/-0.06 in tumor tissue, and 0.71+/-0.14 and 0.16+/-0.04 in normal tissue, respectively. DPD mRNA expression levels were significantly lower in tumor group (0.11+/-0.02) than in normal controls (0.38+/-0.05). There was statistically significant difference in TS and TP mRNA expression levels among different pathological grades and clinical stages (P<0.05), but histological subtype was not significantly associated with TS and TP mRNA expression. DPD gene expression was not significantly associated with any clinicopathological parameters. Immunohistochemistry revealed that TP protein was mainly distributed in nucleus, and TS and DPD mainly in cytoplasm. The protein expression intensity of TS, TP and DPD was coincided with the mRNA expression levels. It was concluded that TS, TP mRNA and protein expression levels were significantly higher in epithelial ovarian cancer, and DPD mRNA and protein expression levels were significantly lower. The expression levels of TS and DPD were related to the patients' prognosis and survival. Combined gene expression levels of TS, TP and DPD represent a new variable to predict the clinical outcome in ovarian cancer. The association of TS, TP and DPD expression levels with survival suggests an importance of these genes for tumor occurrence and progression.

Section: Discussionmentioning

confidence: 99%

Relationship between the expression of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase and survival in epithelial ovarian cancer

Weng

J. Huazhong Univ. Sci. Technol. [Med. Sci.]

et al. 2010

Pharmacokinetic and Pharmacodynamic Analyses of 5-Fluorouracil in East-Asian Patients with Nasopharyngeal Carcinoma

Lin

Zou

et al. 2016

Clin Pharmacokinet

Pharmacogenetics in Oncology: A Promising Field

Houtsma

Guchelaar

Gelderblom

2010

CPD

Pharmacogenetics is a rapidly developing field, especially in oncology. In the most ideal situation pharmacogenetics will allow oncologists to individualize therapy based on patients' individual germline genetic test results. This can help to improve efficacy, reduce toxicity and predict non-responders in a way that alternative therapy can be chosen or individual dose adjustments can be made. Multiple pathways have been studied extensively of which a brief review is presented here. Increased 5FU toxicity is associated with variations in the DPYD gene, TYMS gene and MTHFR gene. Furthermore variations in the UGT1A gene and the ABCB1 gene influence irinotecan metabolism and disposition. Other genetic changes result in reduced DNA repair capacity related to platinum efficacy or reduced cytochrome P450 2D6 activity related to tamoxifen efficacy. Despite the extensive number of pharmacogenetic studies and promising results, it is still unclear when and how pretreatment genetic screening should be implemented in oncology. Future prospective studies should focus on the effect of pharmacogenetics on patient outcome and combine this with cost effectiveness evaluations. Thus supplying us with predictive models helping in deciding when pretreatment genetic screening is useful.