Influence of L-methionine-deprived total parenteral nutrition with 5-fluorouracil on gastric cancer and host metabolism

Abstract

AIM To investigate the influence of L-methioninedeprived total parenteral nutrition with 5-FU on gastric cancer and host metabolism.METHODS N-methyl-N'-nitro-nitrosoguanidine (MNNG) induced gastric cancer rats were randomly divided into four groups: Met-containing TPN group (n = 11), Metdeprived TPN group (n = 12), Met-containing TPN+5-FU group (n = 11) and Met-deprived TPN+5-FU group (n = 12). Five rats in each group were sacrificed after 7 days of treatment and the samples were taken for examination. The remaining rats in each group were then fed separately with normal diet after the treatment until death, the life span was noted.RESULTS The tumors were enlarged in Met-containing group and shrank in Met-deprived group markedly after the treatment. The DNA index (DI) of tumor cells and the body weight (BW) of rats had no significant change in the two groups, however, the ratio of tumor cells' S phase was increased. The ratio of G2M phase went up in Met-containing group, but down in Metdeprived group. In the other two groups that 5-FU was added, the BW of rats, and the diameter of tumors, the DI of tumor cells, the S and G2M phase ratio of tumor cells were all decreased, particularly in Metdeprived plus 5-FU group. Pathological examination revealed that the necrotic foci of the tumor tissue increased after Met-deprived TPN treatment, and the nucleoli of tumor cells enlarged. In -MetTPN+5-FU group, severe nuclear damage was also found by karyopyknosis and karyorrhexis, meanwhile there was slight degeneration in some liver and kidney cells. The serum free Met and Cysteine decreased markedly (P<0.001), while other amino acids, such as serum free serine and glutamine increased significantly (P<0.005). All the rats died of multiple organ failure caused by cancer metastasis. The average survival time was 18.6 days in Met-containing TPN group, 31 days in Metdeprived TPN group, 27.5 days in Met-containing TPN+5-FU group, and 43 days in Met-deprived TPN+5-FU group (P<0.05).

Oral Recombinant Methioninase Sensitizes a Bladder Cancer Orthotopic Xenograft Mouse Model to Low-dose Cisplatinum and Prevents Metastasis

“…There are two strategies to restrict methionine levels in cancer. One is a methionine-free diet (33), but a long-termlow protein diet cannot maintain basic nutritional needs. Another way to deplete methionine is with methioninase ).…”

Metabolic reprogramming and epigenetic modifications on the path to cancer

“…A methionine-limited diet suppresses tumor invasion and metastasis (Breillout et al, 1987 ; Guo et al, 1996 ; Jeon et al, 2016 ). The combination of a methionine-limited diet and one-carbon metabolism inhibitors, such as 5-fluorouracil (5-FU), has a synergistic effect on tumor inhibition (Hoshiya et al, 1997 ; Xiao et al, 2001 ). Methionine supplementation in tumors restores T-cell function in B16F10 tumor-bearing mice and retards tumor growth (Bian et al, 2020 ).…”

Dietary Manipulation of Amino Acids for Cancer Therapy

“…Dietary Met restriction has shown anticancer activity in numerous preclinical studies [26,27,34,39,40,. A dietary Met depletion (0%) induced anticancer activity in rats [39,[121][122][123][124] and mice [105][106][107][108][109][110][111]125] with different types of cancer. The force feeding of a diet lacking in Met for 5 days reduced tumor growth by 39% in the Walker rat model, but this diet caused the animals to lose l-2 g weight/day [39].…”

“…Since Met is necessary for biosynthesizing Cys, the dietary levels of Cys can condition the dietary requirements of Met. A dietary restriction of Met can increase the antitumor effects of a variety of drugs, including 5-fluorouracil [106,114,117,121,124], anti-PD-1 immunotherapy [34,118], vincristine [122], cisplatin [105], lexatumimab (TNFα receptor agonist) [109], auranofin (TXNRDs inhibitor) [110], ethionine (Met analog) [123], and radiotherapy [114]. Table 3 shows representative studies assessing the in vivo anticancer activity of Met restriction.…”