S-1, an oral fluoropyrimidine, enhances radiation response of DLD-1/FU human colon cancer xenografts resistant to 5-FU.
S-1, a novel oral fluoropyrimidine, is increasingly used for the treatment of human cancer including gastrointestinal carcinomas. Using the 5-FU resistant DLD-1/FU human colon cancer cell xenografts, the present study investigated whether S-1 enhances the therapeutic efficacy of radiation and if so what are the underlying mechanisms. Nude mice bearing tumor xenografts were treated with radiation, S-1, or both. Tumor growth delay was the treatments' endpoint. To determine whether S-1 enhances intrinsic cell radiosensitivity, we performed clonogenic cell survival assay. Also we assessed the expression of thymidylate synthase (TS) using immunohistochemistry assay. While S-1 or 5 Gy were only slightly effective as single agents in delaying tumor growth, the combined treatment was highly effective. Clonogenic cell survival showed that S-1 strongly enhanced cell radiosensitivity. Immunohistochemistry showed that the expression of TS was down-regulated in tumors treated by S-1 plus radiation. Combined S-1 plus radiation treatment resulted in a synergistic effect in the therapy of 5-FU resistant human colon carcinoma xenografts (EF = 2.06). The effect could be attributed to the ability of S-1 to increase cell radiosensitivity (EF = 1.9) and to the down-regulation of TS involved in cellular processes leading to radio- and (or) chemo-resistance.
Nakata
Eiko
E
Tohoku University Biomedical Engineering Research Organaization, Miyagi 980-8575, Japan.
Fukushima
Masakazu
M
Takai
Yoshihiro
Y
Nemoto
Kenji
K
Ogawa
Yoshihiro
Y
Nomiya
Takuma
T
Nakamura
Yasuhiro
Y
Milas
Luka
L
Yamada
Shogo
S
D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010094:Oxonic Acid / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D005641:Tegafur / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D011838:Radiation-Sensitizing Agents; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D005472:Fluorouracil