One of the target genes of pemetrexed (PEM), thymidylate synthase (TS), has been shown to have a close association with its efficacy. p=0.518; DCR, p=0.631; ORR, p=0.541), as well as those with a 6-bp insertion and 6-bp deletion (PFS, p=0.776; DCR, p=0.626; ORR, p=0.330). To study the combined effect of TS polymorphisms, the study populace was divided into three TAK-733 groups: 2R&6 del, 2R&6 ins and 3R&6 del. No significant differences were observed among the different groups according to DCR (p=0.517), ORR (p=0.611) and PFS (p=0.938). In conclusion, polymorphisms of the TS gene do not appear to be a prognostic marker for advanced NSCLC patients receiving PEM-based treatment. source of thymidylate synthesis, is an essential enzyme involved in DNA replication and cell growth (1). It catalyzes the conversion of deoxyuridylate (dUMP) to deoxythymidylate (dTMP), which is critical for DNA synthesis and repair. The substrate for TS is usually a central metabolite in folate metabolism. Due to its important role in the folate biosynthesis pathway, it has become one of the major targets of antitumor brokers, such as 5-fluorouracil (5-Fu) and pemetrexed (PEM). PEM is usually a multitarget antifolate agent that has produced excellent clinical outcomes in first-line, second-line and maintenance treatment in advanced non-small cell lung cancer (NSCLC) (2C4). Notably, PEM-based treatment provided more favorable clinical outcomes in patients with adenocarcinoma (ADC) compared with those with squamous cell carcinoma (SCC). A post hoc analysis of three randomized global trials confirmed the superiority of PEM in non-squamous non-small cell lung cancer (NSNSCLC) (5). A plausible explanation for this superiority may involve the expression of TS in different histological types. A Japanese study (6) collected 2621 NSCLC patients and examined TS expression in postoperative tissue samples obtained from this populace. TS expression was categorized according to TS/-actin values. In univariate analysis, TS gene expression in formalin-fixed and paraffin-embedded (FFPE) tumor samples was higher for SCC (mean TS/-actin 4.3), compared with ADC (mean TS/-actin 2.3) (p<0.01). Another study also confirmed that this mean scoring of TS was significantly higher in the non-ADC than in the ADC subgroup (2.790.61 vs. 1.980.88, p<0.0001) (7). Notably, the above analysis revealed that patients with positive expression TAK-733 of TS had a lower 5-12 months progression-free survival (PFS) rate than those presenting negative expression of TS (48.6 TAK-733 vs. 79.1%, p<0.0001). The 5-12 months overall survival (OS) rate TAK-733 was also significantly lower in the positive group (67.5 vs. 86.1%, p=0.0002). Among patients with ADC, the 5-12 months PFS rate was 30.5% in the TS expression positive group and 83.1% in the negative group (p<0.0001). The 5-12 months OS rates were 61.1 and 90.1%, respectively (p<0.0001). Sun (8) also exhibited an association between a higher response rate for PEM-based chemotherapy and TS-negativity (33.7 vs. 14.1%, p=0.002). PFS for PEM-based treatment was significantly longer in the ADC populace (2.9 vs. 1.4 months, p=0.001) and TS-negative subgroup (4.1 vs. 2.0 months, p=0.001). Multivariate analysis revealed that TS-negativity was associated with longer PFS [hazard ratio (HR), 0.70; 95% confidence interval (CI), 0.51C0.97]. The functional polymorphisms in the TS gene have been suggested to be a regulator of downstream protein expression and mRNA level (9,10). The most closely studied polymorphisms have focused on the variable number of tandem repeats (VNTR) of a 28-bp sequence (2R/3R) in the 5-untranslated region (UTR), a single nucleotide Rabbit polyclonal to LRRC48. polymorphism (SNP) in the second repeat of 3R allele (G>C) and a 6-bp deletion or insertion in 3-UTR of the TS gene. Preclinical study revealed that this triple repeat occurring in 5-UTR plus the 6-bp insertion conferred a higher transcriptional efficiency and greater mRNA stability than the double repeat plus 6-bp deletion (10,11). The association between these polymorphisms and efficacy of 5-Fu-based chemotherapy has been exhibited in certain solid tumors, such as gastric, colorectal and breast malignancy (12C14). A previous study suggested that VNTR and SNP in the 5-UTR of the TS gene in combination with a C667T polymorphism of methylenetetrahydrofolate reductase (MTHFR) were associated with prognosis of NSCLC (15). However, there was no difference in prognosis between different genotypes when TS and MTHFR groups were considered separately. Based on the data mentioned above, the present study was conducted to further investigate the association between polymorphisms of the TS gene and efficacy of PEM-based treatment in advanced NSCLC. Materials and methods.