Thymidylate synthase and dihydropyrimidine dehydrogenase in non-small cell lung cancer: relationship between mRNA expression and activity.
BACKGROUND
UFT (Tegafur + Uracil) has been reported to be effective for postoperative adjuvant chemotherapy of non-small cell lung cancer (NSCLC) in a randomized prospective study. Recently, many clinical studies have demonstrated that UFT is effective for cancer with a low activity of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD). In the present study, we investigated TS and DPD activity in resected tumors and corresponding normal lungs and the relationship between the activity and the mRNA expression of TS and DPD in NSCLC.


METHODS
Seventy-seven patients underwent complete surgical resection and lymph node dissection for NSCLC. The activity of TS was determined by the FdUMP binding assay combined with gel filtration. The activity of DPD was determined by radio-enzymatic assay. Tumor tissues and their paired non-cancerous tissues were assayed. Furthermore, the mRNA expressions of TS and DPD were examined by real-time RT-PCR.


RESULTS
The mean TS and DPD activities in NSCLC were approximately 2.4-fold and 5-fold of those in normal lungs. The mean TS and DPD activities of NSCLC were 0.099 pmol/mg and 407 pmol/mg/min, respectively. Although both TS and DPD activities showed a tendency to be high for adenocarcinoma, there was no significant difference between TS and/or DPD activities and any clinical findings (age, gender, stage and histological type). The mRNA expression of DPD was correlated with DPD activity (rs=0.846, p<0.001). The mRNA expression of TS was weakly correlated with TS activity (rs=0.757, p<0.001).


CONCLUSIONS
TS and DPD activities in NSCLC were higher than those in normal lungs. Assay of DPD mRNA and TS mRNA by real-time RT-PCR can be used as an indicator for the use of UFT.
Miyoshi
Takanori
T
Department of Oncological and Regenerative Surgery, School of Medicine, University of Tokushima, Kuramoto-cho, Tokushima 770-8503, Japan.
Kondo
Kazuya
K
Fujino
Haruhiko
H
Takahashi
Yuji
Y
Sawada
Naruhiko
N
Sakiyama
Shoji
S
Tsuyuguchi
Masaru
M
Kimura
Suguru
S
Sumitomo
Masayuki
M
Monden
Yasumasa
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008168:Lung / Q000201:enzymology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000601:surgery; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000627:therapeutic use; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013940:Thymidylate Synthase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
D011743:Pyrimidines; D012333:RNA, Messenger; C029269:5-fluoropyrimidine; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase