| Objective:The objective of the study was to examine the health-related quality of life and immune function during treatment in patients with gastric or rectal cancer who receive FOLFOX4and Fuzheng Yiliu Granules(FYG) and to examine the antitumor activity and biological mechanisms of FYG in vitro and in vivo.Methods:1. Hepatoma22(H22) tumor-bearing mice were treated with FYG (18g/kg, ig),5-FU (10mg/kg, ip), or5-FU plus FYG for5days. The relative tumor proliferation rates and weight were measured. White blood cell (WBC) and lymphocyte (LY) were counted. Percentages of immune cells in the peripheral blood and cytokines (IL-2) and TNF-a in the serum were measured. The apoptosis of tumor tissue was determined. The apoptosis of tissue was examined by TUNNEL. Protein expression of apoptosis factors (Bax,Bcl-2) and TS (5-FU target enzyme) were evaluated by immunhistochemistry. Transcription of apoptosis factors (Bax,Bcl-2, p53,C-myc) and TS was evaluated by RT-PCR.2. FYG along and FYG plus5-FU were administrated to HepG2cell line with different dosage for24h,48h and72h respectively and then the cell viability was detected by MTT. FYG-containing serum was prepared from SD rats treated for7days (high dose:25.2g/kg; intermidiate dose:12.6g/kg; low dose:6.3g/kg). Cell cycle, cell viability and apoptosis were evaluated after HepG2cells were cultured in FYG-containing serum for48h. The levels of IL-2and TNF-a in FYG-containing serum were also determined.3. Patients with gastric or rectal cancer who receive FOLFOX4were randomized into2groups. Patients in the TCM group received additional FYG. Patients in the control group received placebo. Health-related quality of life was assessed at baseline (pre-treatment) and at5-week intervals during treatment, using the European Organization for Research and Treatment of Cancer QLQ-C30questionnaires. Health-related quality of life data for five courses of treatment were then analyzed longitudinally. At baseline, at4-week,8-week after chemotherapy and the end of the study to examine the percentage of T lymphocyte subsets in peripheral blood (CD3, CD4, CD8,Treg), NK and concentrations of immunoglobulin (IgA, IgG, IgM), and complement (C3, C4). Results:1. FYG had no apparent toxicity. FYG alone had antitumor effect and could induce apoptosis (P<0.05, vs vehicle group). Combination of5-FU and FYG produced a more potent antitumor effect and caused more marked apoptosis in tumor tissue (compared with vehicle, P<0.01; compared with5-FU or FYG, P<0.05), although no synergistic effect was observed. Mice treated with5-FU plus FYG had higher thymus index (P<0.05) compared with the vehicle group. The numbers of both WBC and LY were decreased by5-FU (compared with vehicle, P<0.01), which was significantly reversed after FYG was administered (5-FU+FYG vs5-FU, P<0.01and P<0.05, FYG vs vehicle, P<0.01). FYG significantly increased the percentages of CD3+(P<0.01), CD4+(P<0.01), natural killer (NK; P<0.01) and ratio of CD4+/CD8+(P<0.05) compared with the vehicle group. Combination of5-FU and FYG increased the percentages of CD3+, CD4+, and ratio of CD4+/CD8+compared with the vehicle group (P<.01) and the percentages of CD3+, NK, and ratio of CD4+/CD8+compared with the5-FU group(P<0.05). Mice receiving FYG alone or FYG plus5-FU had higher serum levels of TNF-a (P<0.01) compared with the vehicle. Compared with vehicle group, expression of Bax in FYG group,5-FU group and5-FU+FYG group was significant up-regulated(P<0.05or P<0.01). The expression of p53in5-FU group and5-FU+FYG group and the Bax gene in FYG group and5-FU+FYG group were higher than model group(P<0.05or P<0.01).2. The polysaccharide content in FYG was about63%, the FYG alone or in combination with5-FU in vitro did not show any anti-tumor effect. FYG serum significantly decreased HepG2cell viability, inhibited cell proliferation (P<0.05) and induced apoptosis (P<0.01). In addition, the levels of IL-2and TNF-a (P<0.01) of high dose serum were higher than the blank serum.3. Eighty-five patients (50in the TCM group and35in the control group respectively) completed the baseline and post-treatment health-related quality of life assessments. The post-treatment assessments changed significantly from the baseline values in both groups. The post-treatment assessments favored the TCM group for the total scales (P=0.040) and fatigue and appetite scales (P<0.05). After treatment, CD3, CD4, CD4/CD8, IgG, IgA, IgM, C3, NK cells showed significant increase (P<0.05), CD8and C4had no significant changes (P>0.05); Treg was significantly decrease (P<0.05). Compared with the control group, CD3, CD4, CD4/CD8, IgG, IgA, and C3, NK cells showed significant differences (P<0.05).Conclusions:1. FYG can regulate the immune function while alleviating its side effects and induce the apoptosis of tumor in Hepatoma22tumor-bearing mice during adjuvant chemotherapy with5-FU2. FYG extract did not inhibit the tumor cell proliferation and promote apoptosis until it was metabolized in vivo.3. Overall health-related quality of life was improved and immune system was modulated by FYG during adjuvant chemotherapy with oral uracil/tegafur plus leucovorin in patients with gastric or rectal cancer. |
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