Pretreatment with S-1, an oral derivative of 5-fluorouracil, enhances gemcitabine effects in pancreatic cancer xenografts.
BACKGROUND
The systemic administration of gemcitabine (GEM) has been accepted as a standard treatment for patients with advanced pancreatic cancer. The major mediator of cellular uptake of GEM is the human equilibrative nucleoside transporter 1 (hENT1) whose expression is up-regulated by thymidylate synthase inhibitors, such as 5-fluorouracil (5-FU). S-1 is a novel oral derivative of the 5-FU prodrug tegafur combined with two modulators. Recent clinical trials have reported the promising effect of S-1 in pancreatic cancer. The purpose of this study was to evaluate the relationship between different schedules and the effects of GEM/S-1 combination therapy on pancreatic cancer xenograft models.


METHODS
Human pancreatic tumor xenografts were prepared by subcutaneous implantation of MiaPaCa-2 into nude mice. Expression of hENT1 was determined by quantitative RT-PCR. GEM cellular uptake was determined using [3H] GEM.


RESULTS
Significant increases in hENT1 expression and GEM cellular uptake were observed after S-1 treatment. Six different treatment schedules (no treatment, single agent of GEM or S-1, combination treatment with GEM either before, simultaneously or following administration of S-1) were compared. Significant tumor growth inhibition was observed in the mice treated with S-1 followed by GEM compared to either untreated mice or the mice treated with the other schedules.


CONCLUSIONS
Based on the effects of S-1 on the uptake of GEM, S-1 should be used before GEM treatment. The GEM/S-1 combination therapy in patients with pancreatic cancer may be promising and should be tested in clinical trials.
Nakahira
Shin
S
Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, E2, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Nakamori
Shoji
S
Tsujie
Masanori
M
Takeda
Setsuo
S
Sugimoto
Keishi
K
Takahashi
Yuji
Y
Okami
Jiro
J
Marubashi
Shigeru
S
Miyamoto
Atsushi
A
Takeda
Yutaka
Y
Nagano
Hiroaki
H
Dono
Keizo
K
Umeshita
Koji
K
Sakon
Masato
M
Monden
Morito
M
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004357:Drug Synergism; D033721:Equilibrative Nucleoside Transporter 1 / Q000096:biosynthesis / Q000235:genetics; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010094:Oxonic Acid / Q000008:administration & dosage; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D005641:Tegafur / Q000008:administration & dosage; D014316:Tritium; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D004338:Drug Combinations; D033721:Equilibrative Nucleoside Transporter 1; D012333:RNA, Messenger; C438649:SLC29A1 protein, human; D003841:Deoxycytidine; D014316:Tritium; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D005472:Fluorouracil; D000093542:Gemcitabine