Capecitabine metronomic chemotherapy inhibits the proliferation of gastric cancer cells through anti-angiogenesis

Abstract

To evaluate the inhibitory effect and mechanism of capecitabine metronomic chemotherapy on gastric cancer cells. In vitro, the effects of 5-fluorouracil (Fu) metronomic chemotherapy on proliferation, apoptosis, tube formation ability, and angiogenesis were detected. In vivo, Ki-67, CD34 and VEGF were detected by immunohistochemical staining (IHC). Flow cytometry was used to detect the percentage of circulating endothelial progenitors (CEPs), and VEGF and PDGF were detected by ELISA in the peripheral blood of nude mice. The proliferation of the SGC-7901 and AGS gastric cancer cell lines in the metronomic 5-Fu group was decreased compared with the control group in vitro. The total length of the small tubes and tubular junction numbers were significantly lower in the metronomic group than the control group. The VEGF and PDGF levels in the cell culture supernatants were lower in the metronomic group than the control group. Compared with the control group, the CEP percentage was decreased in the peripheral blood of tumor-bearing nude mice following treatment with metronomic 5-Fu or capecitabine chemotherapy. No significant changes were found in the conventional or control group. In the peripheral blood of tumor-bearing nude mice, the VEGF and PDGF levels were decreased in the metronomic groups. Metronomic 5-Fu inhibited the proliferation of gastric cancer cells in vitro and in vivo, and their antitumor effects were non-inferior to those of conventional dose chemotherapy, with mild side effects. Thus, tumor inhibition may be attributed to anti-angiogenesis.

Metronomic chemotherapy remodel cancer‑associated fibroblasts to decrease chemoresistance of gastric cancer in nude mice

“…4B). These results correspond with those of our previous study revealing that it is 5-FU and capecitabine metronomic chemotherapy rather than 5-FU and capecitabine traditional chemotherapy that decrease the MVD in the GC xenografts (9). The mean densities of VEGF in the 5-Fu MTD, 5-Fu LDM, capecitabine MTD, capecitabine LDM and control groups were 0.016±0.001, 0.0066±0.0001, 0.063±0.001, 0.012±0.001, and 0.063±0.001, respectively (Fig.…”

“…Our previous studies have confirmed that metronomic 5-Fu-based chemotherapy may perform an anti-angiogenetic role, which is associated with the antitumor effects of metronomic chemotherapy in vivo and in vitro. Compared with the conventional dose traditional chemotherapy, the antitumor effect of low dose metronomic chemotherapy is not inferior to the former (8,9). In addition to the anti-angiogenetic effect, it was speculated that there are other factors that enhance the antitumor effect of low-dose groups.…”

“…Capecitabine is a precursor of 5-Fu and exhibits antitumor effects via conversion by the thymidine phosphorylase enzyme in cancer cells (8). To be an oral cytotoxic agent, capecitabine has significant merits compared with intravenous drugs with regards to being an appropriate choice for metronomic chemotherapy (9). The characteristics of better efficacy, low toxicity and good compliance, which have been confirmed, made metronomic chemotherapy a novel trend in tumor chemotherapy (8,9).…”

“…Metronomic chemotherapy not only disrupts the process of cell division, which inhibits the proliferation of cancer cell, but also eliminates endothelial cells involved in angiogenesis, termed an anti-angiogenetic effect (7). In our previous studies, capecitabine and 5-fluorouracil (5-Fu) was able to express a marked anti-angiogenetic effect when administered at defined doses and schedules in mice xenografts of (8,9). Besides tapering the tumor growth, the anti-angiogenetic activity of metronomic chemotherapy was able to overcome drug resistance (10).…”

“…The nude mice were randomly divided into the following groups: i) Control group, intraperitoneally injected with normal saline; ii) 5-Fu conventional dose group [5-Fu maximum tolerated dose (MTD) group], intraperitoneally injected with 50 mg/kg, twice per week for 2 weeks, with a 1 week discontinuation for 6 weeks; iii) 5-Fu metronomic group [5-Fu low-dose metronomic (LDM) group], intraperitoneally injected with 15 mg/kg, twice a week for 6 weeks; iv) capecitabine (Roche Diagnostics, Shanghai, China) conventional dose (capecitabine MTD group), intragastric 500 mg/kg, twice per week for 2 weeks, with a 1 week discontinuation for 6 weeks; and v) capecitabine metronomic group (capecitabine LDM group), intragastric administration at 200 mg/kg, twice a week for 6 weeks. Following drug administration, a Vernier caliper was used to measure the length (L) and short track (W) of the tumor mass every 7 days in order to calculate the volume (V) according to the following formula: V=(W + L)/(2 x W x L x 0.5236) (9). Tumor size did not exceed 20 mm in any direction.…”