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.

Therapeutic strategies with oral fluoropyrimidine anticancer agent, S-1 against oral cancer

“…As a result, we clarified S-1 could exert anti-angiogenic effects via up-regulation of TSP-1. Moreover, we also demonstrated that alternate-day administration of S-1 is more useful than consecutive-day administration in terms of anti-angiogenic effects [58]. Our findings suggested that S-1 might fit with the concept of metronomic chemotherapy in oral cancer treatment [58], [59] (Fig.…”

“…Moreover, reduction of microvessel density, and induction of TSP-1 expression was markedly seen in alternate days treated tumors than in the four-week treatment and two-week rest, the two-week treatment and one-week rest treated tumors. As alternate days treatment of S-1 could exert remarkable anti-angiogenic effects via up-regulation of TSP-1, we believe S-1 may fit with the concept of metronomic chemotherapy in oral cancer treatment [58] (Fig. 7).…”

“…Also, we have reported that alternate days treatment regimen with S-1 was more useful than four-week treatment and two-week rest or two-week treatment and one-week rest regimen with S-1 as a metronomic chemotherapy [58] (Fig. 7).…”

Antitumor effects of bevacizumab in combination with fluoropyrimidine drugs on human oral squamous cell carcinoma

“…On the other hand, the results of the current in vivo experiments suggested that the anti-angiogenic action of bevacizumab and the antitumor effect of S-1 synergistically inhibited tumor cell proliferation and promoted apoptosis. Although VEGF-A expression was not analyzed in mice tumors, it may be possible that S-1/5-FU downregulated VEGF expression by suppressing NF-κB, which finally resulted in decreased MVD and inhibited angiogenesis ( 8 , 45 ).…”

Metronomic Therapy in Oral Squamous Cell Carcinoma

“…One compound is a 5-fluorouracil (5-FU) prodrug, tegafur. The other two are gimeracil (inhibits the 5-FU degradation) and oteracil (lowers the gastrointestinal toxicity of 5-FU) [85]. In an in vitro study, Ferdous et al first demonstrated that more frequent 5-FU dosing (16h treatment, 8h rest vs. 96h treatment, 48h rest or 48h treatment, 24h rest) did not result in more cytotoxic cell death according to3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H tetrazolium bromide assay.…”