5-fluorouracil + semustine + triazinate

This is a combination chemotherapy regimen consisting of three small-molecule agents: - **5-fluorouracil** (5-FU): an antimetabolite that inhibits thymidylate synthase, interfering with DNA and RNA synthesis, primarily used in the treatment of gastrointestinal cancers. Its cytotoxicity in GI cancers is now understood to be mainly due to incorporation into RNA, leading to an RNA damage response and cell death. - **Semustine** (MeCCNU): a nitrosourea alkylating agent that crosslinks DNA strands by forming interstrand crosslinks and monoadducts, thereby inhibiting DNA replication and transcription. It is associated with significant hematologic toxicity and carcinogenic risk. - **Triazinate** (trimetrexate): a non-classical antifolate that inhibits dihydrofolate reductase (DHFR), blocking folate metabolism required for nucleotide synthesis. This combination has been studied as part of multi-drug regimens for advanced gastric cancer and colorectal cancer. In clinical trials, combinations including these drugs have shown limited efficacy improvements over other regimens but are associated with notable toxicities such as hematologic suppression.