cisplatin/fluorouracil
cisplatin/fluorouracil
Overview
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 B-cell lymphoma 2-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 PD-L1 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.
Focus of Latest Publications
cisplatin combined with fluorouracil remains a standard chemotherapy regimen for advanced head and neck and esophageal squamous cell carcinomas, particularly when delivered concurrently with radiotherapy. Clinical studies have increasingly focused on individualizing cumulative cisplatin dosing based on renal function, as glomerular filtration rate predicts treatment tolerance and therapeutic outcomes. In metastatic colorectal cancer, fluorouracil with leucovorin enhancement continues as a backbone therapy, though real-world survival and toxicity data remain incompletely characterized. A practical challenge in cisplatin-based regimens is chemotherapy-induced nausea and vomiting, for which aprepitant prophylaxis has demonstrated efficacy in high-emetogenic combinations. Recent evidence supports the feasibility of concurrent cisplatin/fluorouracil chemoradiotherapy in elderly patients with synchronous hypopharyngeal and esophageal cancers, with high treatment completion rates and favorable response despite substantial toxicity requiring temporary suspension in some cases.
Acquired cisplatin resistance remains a major barrier to therapeutic success across multiple malignancies, with recent studies identifying diverse molecular mechanisms. In ovarian cancer, DLL1-mediated ferroptosis resistance through the Notch-Nrf2/GPx4 axis contributes to treatment failure. Cancer-associated fibroblasts promote cisplatin resistance in esophageal cancer via elevated S100A4 expression, a relationship that can be therapeutically targeted to restore chemosensitivity. Nasopharyngeal carcinoma cells with low SLC44A4 expression exhibit reduced sensitivity to cisplatin and other DNA-damaging agents, while microRNA dysregulation predicts platinum resistance in lung cancer. In newly established tongue squamous cell carcinoma models, TP53 mutational status and altered expression of proliferation-related genes correlated with differential cisplatin sensitivity.
Multiple adjunctive strategies have emerged to enhance platinum efficacy or overcome resistance. Electroporation combined with cisplatin increases neuroblastoma cell killing in vitro, particularly with concurrent inhibition of DNA repair. Marine-derived and plant-derived natural products—heteronemin in oral squamous cell carcinoma, santamarine in oral cancer, and Paris polyphylla saponin II in cervical cancer—demonstrate enhanced anticancer activity compared to single-agent cisplatin or fluorouracil through ROS-mediated apoptosis and ferroptosis-associated mechanisms. Novel platinum(IV) prodrug complexes incorporating dual CDC25A/NF-κB inhibitory or sulfasalazine-derived ligands show superior antitumor activity and overcome cisplatin resistance in ovarian and triple-negative breast cancers through multimodal cell death pathways. Saquinavir enhances cisplatin cytotoxicity in lung adenocarcinoma by reducing claudin-2-mediated chemoresistance, while dexmedetomidine potentiates cisplatin in esophageal carcinoma through pyroptotic pathway activation.
Additional approaches address cisplatin-associated toxicity and enable localized delivery. cisplatin-induced acute kidney injury can be mitigated using traditional Chinese medicine formulations targeting NF-κB-dependent renal inflammation. Hypotonic cisplatin lavage following marginal resection shows preliminary efficacy for preventing local recurrence in soft tissue sarcomas. For hepatocellular carcinoma refractory to immunotherapy, balloon-occluded transarterial chemoembolization with cisplatin-gelatin particles provides an alternative locoregional treatment strategy.