Cisplatin/fluorouracil

Cisplatin/fluorouracil (CF) is a combination chemotherapy regimen pairing two of oncology's most foundational cytotoxic agents: cisplatin, a platinum-based DNA-crosslinking compound, and fluorouracil (5-FU), a fluoropyrimidine antimetabolite that disrupts RNA synthesis and thymidylate synthase activity. Together, these agents exert complementary mechanisms of cytotoxicity — cisplatin generates intrastrand and interstrand DNA adducts that trigger apoptotic cascades (including activation of BCL2 apoptosis regulator-regulated pathways and cysteine-aspartic acid protease 3), while fluorouracil interferes with nucleotide metabolism and RNA processing. The synergy of these two mechanisms has made CF a backbone regimen across a broad spectrum of squamous cell and adenocarcinoma histologies, including cancers of the head and neck, esophagus, hypopharynx, stomach, cervix, and lung.

Despite its clinical longevity, the CF regimen carries a significant toxicity burden. cisplatin is associated with nephrotoxicity — partly mediated through disruption of proximal tubule metabolic function and TAK1-dependent NF-κB signaling — as well as emetogenicity and neurotoxicity. fluorouracil contributes mucositis, myelosuppression, and cardiotoxicity risk. Platinum resistance, immune escape via CD274 molecule upregulation, and the immunosuppressive tumor microenvironment further limit the regimen's long-term efficacy, driving active investigation into next-generation strategies that augment or replace conventional CF chemotherapy.