S-1 mediates the inhibition of lymph node metastasis in oral cancer cells.
S-1, an oral fluorouracil antitumor drug, is composed of three agents: tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo). Approximately 50% of oral squamous cell carcinomas (OSCC) exhibit cervical lymph node metastasis. The extent of lymph node involvement is a major determinant in both staging and prognosis of the majority of OSCC. The purpose of this study was to examine the effect of S-1 on the metastatic potential of OSCC cells. We used orthotopic green fluorescence protein (GFP) SAS-L1, in BALB/c nu/nu mice. Mice received oral doses of either 5% hydroxypropylmethylcellulose (HPMC) for control or S-1 (20 mg/kg) and were autopsied at 2 weeks. We also performed in vitro experiments using concomitant 5-fluorouracil (5-FU) and CDHP as a drug model of S-1 to determine the effect of S-1 on OSCC invasion and metastasis. Although 100% (11 of 11) of mice not treated with S-1 showed cervical lymph node metastasis, only 54.4% (6 of 11) of S-1 treated mice demonstrated metastasis. In in vitro experiments, OSCC cells treated with 5-FU and CDHP showed a marked reduction in invasiveness and in adhesion to laminin coated plates. Western blot analysis revealed that treatment with 5-FU and CDHP suppressed expression of integrins alphav, alpha3, alpha6, beta1, beta3, beta4, beta5, and beta6. These results suggest that S-1 inhibits tumor proliferation and lymph node metastasis in OSCC cells. Moreover, expression of integrin subunits and the integrin signal transduction pathway may be closely related to metastasis suppression.
Sato
Hana
H
Department of Oral and Maxillofacial Surgery, School of Dentistry, Showa University, Tokyo 145-8515, Japan.
Hatori
Masashi
M
Ando
Yuriko
Y
Kurihara
Yuji
Y
Takayama
Sayaka
S
Shirota
Tatsuo
T
Tachikawa
Tetsuhiko
T
Shintani
Satoru
S
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D004338:Drug Combinations; D015870:Gene Expression / Q000187:drug effects; D049452:Green Fluorescent Proteins; D006801:Humans; D016023:Integrins / Q000096:biosynthesis / Q000187:drug effects; D008207:Lymphatic Metastasis / Q000517:prevention & control*; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000473:pathology*; D010094:Oxonic Acid / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D005641:Tegafur / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D016023:Integrins; D049452:Green Fluorescent Proteins; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid