Schedule-dependent therapeutic effects of gemcitabine combined with uracil-tegafur in a human pancreatic cancer xenograft model.
OBJECTIVE
Gemcitabine is taken up by cells mainly via human equilibrative nucleoside transporter 1 (hENT1). Pretreatment of cancer cell lines with 5-fluorouracil (5-FU) leads to an increase in the expression of hENT1 and augments the effect of single-agent gemcitabine treatment in vitro. The purpose of the present study was to evaluate the relationship between the schedules of gemcitabine/uracil-tegafur (UFT) combination therapy and their effects in pancreatic cancer in vivo.


METHODS
The expression level of hENT1 mRNA was examined using 6 types of human pancreatic cancer cell lines treated with 5-FU and MiaPaCa-2 xenograft tumors in BALB/c nu/nu mice treated with UFT. A [H] gemcitabine cellular uptake assay was performed using MiaPaCa-2 cells treated with 5-FU. We compared the effects of 6 different schedules of treatment using UFT and/or gemcitabine on MiaPaCa-2 xenograft tumors.


RESULTS
MiaPaCa-2 cell line was one of the lines that showed the highest rate of 5-FU-induced increase in the hENT1 mRNA level. Gemcitabine uptake was significantly increased when cells were treated with 5-FU. Treatment with UFT significantly increased the hENT1 mRNA expression in MiaPaCa-2 tumors. A significant growth inhibition of MiaPaCa-2 tumors was observed in the mice treated with UFT followed by gemcitabine as compared with either untreated mice or UFT alone-treated mice.


CONCLUSIONS
Our results suggest that the schedule in which the gemcitabine is administered after UFT may be the optimal combination for gemcitabine/UFT treatment in pancreatic cancer.
Tsujie
Masanori
M
Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, E2, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Nakamori
Shoji
S
Nakahira
Shin
S
Takeda
Setsuo
S
Takahashi
Yuji
Y
Hayashi
Nobuyasu
N
Okami
Jiro
J
Nagano
Hiroaki
H
Dono
Keizo
K
Umeshita
Koji
K
Sakon
Masato
M
Monden
Morito
M
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004334:Drug Administration Schedule; D004338:Drug Combinations; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D005641:Tegafur / Q000008:administration & dosage; D014498:Uracil / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D033721:Equilibrative Nucleoside Transporter 1; D012333:RNA, Messenger; C438649:SLC29A1 protein, human; C096910:UFT(R) drug; D003841:Deoxycytidine; D005641:Tegafur; D014498:Uracil; D005472:Fluorouracil; D000093542:Gemcitabine