High intratumoral dihydropyrimidine dehydrogenase mRNA levels in pancreatic cancer associated with a high rate of response to S-1.
OBJECTIVE
Although the prognosis in patients with pancreatic cancer has been poor, we recently reported unusually high response rate and survival benefit of S-1 treatment in patients with pancreatic cancer. The aim of this study was to reveal genetic background of this unique activity of S-1 against pancreatic cancer. S-1 is a novel oral fluoropyrimidine derivative consisting of Tegafur (FT) and dihydropyrimidine dehydrogenase (DPD) inhibitor (5-chloro-2,4-dihydroxypyridine; CDHP). Accordingly, intratumoral DPD mRNA expression level was measured to reveal whether the level in pancreatic cancer was different from other GI cancer and whether it was relevant to chemosensitivity.


METHODS
Thirty-three recurrent pancreatic cancer patients treated with S-1 were studied. We obtained 15 responders and 13 non-responders according to the change of serum CA19-9. The mRNA was extracted from paraffin-embedded surgical specimens using laser captured microdissection, and relative expression levels of each DPD/beta-actin were measured using a quantitative reverse transcription polymerase chain reaction (RT-PCR) (Taqman) system. Forty-four colorectal cancer patients and 20 gastric cancer patients treated with S-1 were enrolled as control groups. Thymidylate synthase (TS) mRNA expression levels were also measured.


RESULTS
Intratumoral DPD mRNA expression level was significantly higher in pancreatic cancer than that in colorectal cancer (P = 0.0003; median level, 1.38 vs. 0.44) and gastric cancer (P = 0.0061; 1.38 vs. 0.82). No difference in TS mRNA expression levels was observed among cancer types. DPD expression among responded pancreatic cancer was significantly lower than non-responded. (P = 0.012, Mann-Whitney U test).


CONCLUSIONS
Intratumoral DPD mRNA expression level in pancreatic cancer was significantly higher than the other malignancies. This result may elucidate possible reasons for the high effectiveness of S-1 in pancreatic cancer.
Kuramochi
Hidekazu
H
Department of Gastroenterology, Tokyo Women's Medical University, Shinjukuku, Tokyo, Japan.
Hayashi
Kazuhiko
K
Uchida
Kazumi
K
Nakajima
Go
G
Hatori
Takashi
T
Danenberg
Kathleen D
KD
Danenberg
Peter V
PV
Yamamoto
Masakazu
M
D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D018395:CA-19-9 Antigen / Q000097:blood; D002945:Cisplatin / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000096:biosynthesis / Q000235:genetics*; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D010094:Oxonic Acid / Q000008:administration & dosage; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis*; D012334:RNA, Neoplasm / Q000032:analysis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000201:enzymology / Q000235:genetics; D005641:Tegafur / Q000008:administration & dosage; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D018395:CA-19-9 Antigen; D004338:Drug Combinations; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D042943:Dihydrouracil Dehydrogenase (NADP); D002945:Cisplatin