Dichloroacetate attenuates hypoxia-induced resistance to 5-fluorouracil in gastric cancer through the regulation of glucose metabolism.

In this study, we investigated whether gastric cancer with hypoxia-induced resistance to 5-fluorouracil (5-FU) could be re-sensitized following treatment with low-dose dichloroacetate (DCA), an inhibitor of the glycolytic pathway. The expression profiles of hypoxia-inducible factor-1α (HIF-1α) and pyruvate dehydrogenase kinase-1 (PDK-1) were analyzed in tissues from 10 patients with gastric cancer who had different responses to adjuvant 5-FU treatment. For the in vitro assays, cell viability and apoptosis were evaluated with and without treatment with 20mM DCA in the AGS and MKN45 cell lines, as well as in PDK1 knockdown cell lines. The expression levels of HIF-1α and PDK-1 were both elevated in the tumor tissues relative to the normal gastric tissues of most patients who showed recurrence after adjuvant 5-FU treatment. Cellular viability tests showed that these cell lines had a lower sensitivity to 5-FU under hypoxic conditions compared to normoxic conditions. Moreover, the addition of 20mM DCA only increased the sensitivity of these cells to 5-FU under hypoxic conditions, and the resistance to 5-FU under hypoxia was also attenuated in PDK1 knockdown cell lines. In conclusion, DCA treatment was able to re-sensitize gastric cancer cells with hypoxia-induced resistance to 5-FU through the alteration of glucose metabolism.

5-Fluorouracil, mitomycin-c, and polysaccharide-k versus uracil-ftorafur and polysaccharide-K as adjuvant chemoimmunotherapy for patients with locally advanced gastric cancer with curative resection.

BACKGROUND: Despite the small but significant survival benefit of adjuvant chemotherapy in locally advanced gastric cancer (LAGC), the optimal regimen remains to be determined. We conducted a randomized trial comparing oral (PO) chemoimmunotherapy (CITX) with intravenous (IV) CITX in LAGC patients (stages IB-IIIB) with curative resection (≥ D2 dissection). METHODS: The patients were randomized to the IV (5-fluorouracil 500 mg/m(2) weekly for 24 weeks, mitomycin-C 8 mg/m(2) every 6 weeks × 4) or the PO (uracil-ftorafur (UFT) 400-600 mg/day for 12 months) group. Patients in both groups received PO polysaccharide-K (3 g/day for 4 months). The planned number of patients was 368 for proving the non-inferiority of PO CITX compared to IV CITX for overall survival. RESULTS: The trial was closed prematurely after enrolling 82 patients (44 in the IV group, 38 in the PO group). With a median follow-up of 82 months, there were no significant differences in the 5-year disease-free survival (73% vs. 55%, p = 0.358) and overall survival (77% vs. 66%, p = 0.159) between the 2 groups. The IV group demonstrated a higher incidence of grade 2 or 3 neutropenia, thrombocytopenia, and vomiting. CONCLUSIONS: PO CITX with UFT appeared to be at least non-inferior to 5-fluorouracil and mitomycin-C CITX, with lower toxicity in the adjuvant treatment for LAGC.

5-fluorouracil, mitomycin-C, and polysaccharide-K adjuvant chemoimmunotherapy for locally advanced gastric cancer: the prognostic significance of frequent perineural invasion.

BACKGROUND/AIMS: Although adjuvant chemotherapy has demonstrated small but significant survival benefit in locally advanced gastric cancer in several meta-analyses, optimal chemotherapy regimen remains to be determined. METHODOLOGY: We retrospectively analyzed the survival of 207 gastric cancer patients (stage IB: 19, II: 65, IIIA: 58, IIIB: 28, IV: 37) who underwent 5-fluorouracil (5-FU), mitomycin-C (MMC), and polysaccharide-K (PSK) chemoimmunotherapy (CITX) after curative resection (FM group). The survival of FM group was compared with that of historical control cohort of 103 patients with almost identical stage distribution who received 5-FU and doxorubicin-based chemotherapy (FA group). RESULTS: Five-year disease-free survival and overall survival (OS) of FM group were 58.7% and 59.1%, respectively. Frequent perineural invasion was significantly associated with poor OS (p = 0.01) in multivariate analysis. There was no statistically significant difference in 5-year OS (59.1% vs. 56.2%, p = 0.637) between FM and FA groups. FM group showed superior 5-year OS (84.4% vs. 67.6%, p = 0.019) compared with FA group in stage IB or II patients without significant difference (p = 0.222) in stage IIIA to IV. CONCLUSIONS: 5-FU, MMC, and PSK CITX is as effective as 5-FU and doxorubicin-based chemotherapy. Moreover, frequent perineural invasion seems to be an important poor prognostic factor.