In Vitro Study of the Anti-cancer Effect of Alternate-day 5-Fluorouracil in Head and Neck Cancer Cells

Abstract

Background/Aim: We have previously reported that alternate-day S-1 had comparable effects and milder adverse events than the respective consecutive-day regimen in head and neck cancer (HNC) patients. The aim of this study was to investigate the anticancer effects of both regimens and underlying mechanisms in vitro. Materials and Methods: Two head and neck squamous cell carcinoma (HNSCC) cell lines were treated with 5-FU given on an alternate-day or consecutive-day schedule. The relative inhibition (RI) of tumor growth was calculated. Cell cycle distributions and cyclin expression following 5-FU treatment were analyzed. Results: The RI of both regimens was almost identical. The percentage of cells in S phase was significantly increased in the alternate-day group compared to the consecutive-day group (p<0.001). Conclusion: The cytotoxic effect of alternate-day was equivalent to that of consecutive-day. S-phase arrest was more prominently observed with the alternate-day regimen, which may help maintain 5-FU sensitivity in head and neck cancer cells.Head and neck squamous cell carcinoma (HNSCC) is still lethal because of the high percentage of recurrence and metastasis (1-4). S-1 is a novel oral anticancer agent consisting of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate at a molar ratio of 1:0.4:1, based on biochemical modulation of 5-fluorouracil (5-FU) (1, 5). A phase III study [Adjuvant Chemotherapy with S-1 after Curative Treatment in Patients with Head Neck Cancer (ACTS-HNC) trial] investigated whether adjuvant therapy with S-1 could improve the prognosis in head and neck cancer (6). S-1 was administered daily for 2 weeks, followed by a 1-week rest period. The study showed that adjuvant chemotherapy with S-1 resulted in significantly better overall survival (OS) in patients with locally advanced HNSCC compared to the control arm. However, the S-1 arm was less well-tolerated and the 1-year completion rate of S-1 was only 43.4%. Therefore, treatment completion and tolerance remain unresolved problems. Sakuma et al. reported that S-1 given on an alternate-day schedule can reduce the incidence of adverse effects without compromising the therapeutic effects of S-1 (7). The alternate-day regimen was equivalent to or better than the consecutive-day regimen in patients with other regimens for metastatic pancreatic cancer in a clinical trial (8). Likewise, we conducted a retrospective study of an alternate-day S-1 regimen as adjuvant therapy after surgery and chemoradiotherapy for advanced HNSCC. In that study, we observed that alternate-day S-1 administration caused fewer adverse effects and was tolerable for patients with advanced HNSCC (9). The completion rate was 80.7% and the occurrence of adverse events tended to be less than that reported in the ACTS-HNC trial. Three-year OS and disease-free survival rates were 74.8% and 57.3%, respectively. Other groups also reported that alternate-day S-1 treatment was associated with milder adverse events without compromising therapeutic effectiveness in clini...

Cell quiescence in planarian stem cells, interplay between p53 and nutritional stimuli

“…Five days after irradiation some DjPiwiA -positive cells are still detectable in planarian body region unrelated to the DMC (figure 1 d ). Strikingly, DCM cells are resistant to the treatment with high doses of the genotoxicant 5-fluorouracyl (5FU) (5FU CT6000) [35,36] that specifically affect cells during their transit through the S phase of the cell cycle [37], thus suggesting that DMC cells are someway arrested or cycle at a very slow rate (figure 1 d ). Another scenario in which DMC cells show higher resistance with respect to dispersed neoblasts is following the silencing of the prohibitin 2 homologue DjPhb2 [38].…”

Sub-Lethal 5-Fluorouracil Dose Challenges Planarian Stem Cells Promoting Transcriptional Profile Changes in the Pluripotent Sigma-Class Neoblasts

“…At this point, the still high dUTP/dTTP ratio most probably leads to frequent miss-incorporation of dUTP into the de-novo-synthesized DNA strand [33]. According to the literature, nucleotide unbalance and miss-incorporation produce a condition in which the replication fork progression slows down, producing fork pausing and instability, which, in turn, trigger an S-phase arrest [34] and unfinished DNA replication, thus activating a DNA damage response to avoid entry into mitosis with under-replicated or damaged chromosomes [35]. Indeed, following a massive S-phase entrance, the number of planarian mitotic cells remains low, leading us to hypothesize that the majority of stem cells remain blocked in the S phase of the cell cycle, following SDT-600 treatment.…”

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