Thymidylate synthase, dihydropyrimidine dehydrogenase, orotate phosphoribosyltransferase mRNA and protein expression levels in solid tumors in large scale population analysis

Abstract

Abstract. It has been reported that the expression of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phosphoribosyltransferase (OPRT) may predict the clinical efficacy of 5-fluorouracil (5-FU)-based therapy in cancer patients. We investigated the differences in the mRNA and protein expression of these enzymes in various tumor tissues. A total of 17,613 specimens of head and neck, gastric, colorectal, breast, lung and pancreatic cancer were collected from multiple facilities in Japan, and the mRNA and protein expression levels of the above enzymes were examined in 4,830 and 12,783 of these specimens, respectively. The mRNA levels were analyzed using RT-PCR in laser-captured microdissected formalinfixed paraffin-embedded specimens, while the protein levels were analyzed by enzyme-linked immunosorbent assays. The median values of the relative TS, DPD and OPRT mRNA levels were 2.06, 0.803 and 1.17, respectively, while the median protein levels were 22.1, 134.8 and 3.81 ng enzyme/mg protein, respectively. The carcinomas were classified into two sets of four groups each using the overall median levels of TS and DPD or TS and OPRT as cutoff values. Approximately 60% of the gastric cancers exhibited elevated mRNA and protein expression levels of DPD, while >65% of the colorectal cancers showed low levels of DPD expression. Overall, 75% of the head and neck cancers exhibited high expression levels of DPD. Among the lung and pancreatic cancers, 50-74% showed low TS/high DPD expression. In conclusion, the mRNA expression and protein levels of TS, DPD and OPRT differed according to the type of cancer. The results of this large-scale population analysis are expected to be useful as reference data for predicting the relationship between the respective enzyme levels and the efficacy of 5-FU-based chemotherapy.

Intratumoral Gene Expression of Dihydrofolate Reductase and Folylpoly-C-Glutamate Synthetase Affects the Sensitivity to 5-Fluorouracil in Non-Small Cell Lung Cancer

“…5,[20][21][22] Regarding the sensitivity of TS in gastric cancer and colorectal cancer, sporadic reports have shown no correlation or reverse correlation between the sensitivity to 5-FU and increased TS activity. 23,24 In NSCLC, a positive correlation with TS was reported, but TS activity tends to be lower than in other carcinomas, 14 suggesting that even if TS activity is high, it falls within the range where the effect of 5-FU can be observed.…”

“…5-FU is rapidly degraded by DPD. Due to the higher DPD activity in NSCLC compared to other carcinomas, 14 5-FU alone is less effective, necessitating co-administration of CDHP, for which S-1 was developed. In view of the mechanism of action of 5-FU, the effects of 5-FU are expected to be reduced if expression of the target enzyme TS and the degrading enzyme DPD in tumor tissue is high.…”

“…The quantitative assay of the ve genes of interest (TS, DPD, OPRT, DHFR, and FPGS) using para nembedded sections of resected NSCLC specimens was performed according to the DTP method of Response Genetics (New York, NY, USA). 10 For every specimen, four sets of 10-µm-thick sections and one set of 5-µm-thick sections were prepared from formalin-xed, para n-embedded tissues. The 5-µm-thick sections were stained with hematoxylin and eosin and examined histologically.…”

“…NSCLC has high DPD activity 14 and requires the use of CDHP, an inhibitor of DPD. In an anticancer sensitivity test, the sensitivity effect of adding CDHP was also examined.…”

S-1 Combined with Bi-Weekly Docetaxel for Non-Small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy: A Phase II Study of North Japan Lung Cancer Group (NJLCG0701)

“…In addition, a pooled analysis of S-1 trials found that there was no difference in response to S-1 in combination with cisplatin depending on histological type (Yamamoto et al, 2010). Lung cancer showed relatively high expression of DPD, which causes greater degradation of 5-FU than other cancers (Fukui et al, 2008). Therefore, being a DPD-inhibitory fluoropyrimidine, S-1 might prevent overexpression of TS, which would make it a good candidate for the treatment of squamous cell carcinoma.…”