Serum Metabolomic Profiles Predict Sensitivity and Toxicity to Platinum-Fluorouracil Chemotherapy in a Gastric Cancer Xenograft Model.

Abstract

Background: The mechanisms of chemotherapy sensitivity and toxicity are complex. Metabolomics can better reflect the status of anticancer drugs, tumors, and hosts simultaneously.

Aim: To identify metabolites and metabolic pathways linked to varying sensitivity and toxicity to chemotherapy in gastric cancer.

Methods: Mice were implanted with human gastric cancer cells through subcutaneous xenografting, and then treated with the PF (platinum-fluorouracil) regimen, with saline serving as the control. Tumor growth was monitored by measuring tumor volume, and body weight was recorded on Days 0, 2, 4, 6, and 8. Kidney damage was assessed using H&E staining. To analyze differential responses, PF-treated mice were grouped separately according to chemotherapy sensitivity (high/medium/low via tumor response) and toxicity (high/medium/low via body weight changes). Serum metabolomics was evaluated using Mass Spectrometry.

Results: Platinum-Fluorouracil (PF) chemotherapy significantly reduced tumor weight in mice (164.7 ± 73.5 mg vs. 334.0 ± 107.5 mg; 54.4% inhibition rate), although it also induced notable body weight loss and renal toxicity compared to controls. Serum metabolomic analysis revealed significant differences between PF and control groups, involving metabolites like deoxymethacin and dehydrocorticosterone, associated with AMPK and cortisol synthesis/secretion pathways. Further comparisons highlighted: (1) High- vs. low-sensitivity subgroups differed significantly in metabolites, such as palmitoyl-CoA and indoleacetic acid (linked to AGE-RAGE, insulin resistance, and AMPK pathways). (2) High- vs. low-toxicity subgroups displayed significant metabolic differences, including methylguanosine and methylcytidine (implicated in ferroptosis, ether lipid, and fatty acid metabolism pathways).

Conclusion: The PF regimen effectively inhibits the growth of subcutaneous tumors in nude mice, while causing varying levels of sensitivity and toxicity in tumor chemotherapy. These observed effects of sensitivity and toxicity are linked to underlying metabolic mechanisms.