title: Efficacy of schedule-dependent metronomic S-1 chemotherapy in human oral squamous cell carcinoma cells.
abstract: Metronomic chemotherapy is based on administration of anticancer agents at low-doses at close regular intervals with no prolonged breaks, and aims to inhibit vascular endothelial cells as well as tumor cells. Recently, it was suggested that metronomic chemotherapy exerts anti-angiogenic effects by inducing thrombospondin-1 (TSP-1) and early growth response-1 (EGR-1), and antitumor effects by suppressing cancer stem cells. S-1 is a novel orally administered anticancer drug that is a combination of tegafur, 5-chloro-2, 4-dihydroxypyridine and oteracil potassium for maintaining efficacious concentrations of 5-FU and reducing the serious gastrointestinal toxicity associated with 5-FU. In the present study, we tried to determine the suitable administration method of S-1 against oral squamous cell carcinoma as a metronomic chemotherapy. We performed in vivo experiments in which tumor-bearing nude mice were used to examine the antitumor activity of S-1 (6.9 mg/kg). HSC2 tumors were treated with three different regimens, given as 4-week treatment and 2-week rest (4W-2W, 1 cycle); 2-week treatment and 1-week rest (2W-1W, 2 cycles); or alternate days treatment (1D-1D, 6 weeks). A fourth group served as control. Antitumor effects and body weight changes were compared in each group. Expression of TSP-1, EGR-1, CD31 and CD44 in HSC2 tumors was examined by immunohistochemistry. The treated groups showed higher tumor growth inhibition compared to the control group, and the relative tumor growth inhibition was not different between the treated groups. Briefly, each relative tumor growth inhibition was 32.4% (4W-2W), 39.6% (2W-1W) and 37.0% (1D-1D). During treatment periods, body weights were lower in the mice with 4W-2W or 2W-1W than 1D-1D or control. Moreover, reduction of microvessel density and CD44 expression, and induction of TSP-1 and EGR-1 expression was markedly seen in 1D-1D-treated tumors compared to 4W-2W-, 2W-1W-treated tumors or untreated control tumors by immunohistochemistry. These findings suggest that the 1D-1D regimen is more useful than the 4W-2W or 2W-1W regimen as a metronomic chemotherapy.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan.
authors.forename: Tarannum
authors.initials: T
authors.lastname: Ferdous
authors.forename: Koji
authors.initials: K
authors.lastname: Harada
authors.forename: Takanori
authors.initials: T
authors.lastname: Kin
authors.forename: Toyoko
authors.initials: T
authors.lastname: Harada
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Ueyama
mesh_terms: D059250:Administration, Metronomic; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004338:Drug Combinations; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D006801:Humans; D051379:Mice; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010094:Oxonic Acid / Q000008:administration & dosage*; D005641:Tegafur / Q000008:administration & dosage*; D019700:Thrombospondin 1 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D004338:Drug Combinations; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D019700:Thrombospondin 1; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid