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.

Key Publications

• NEWJun Novel patient-derived tongue squamous cell carcinoma cell lines from non-smokers: 3D and in vivo models for drug response studies. (Medical oncology (Northwood, London, England), 2026, PMID 42371352): "LMSCC16 also harbored two TP53 mutations and showed increased resistance to Cisplatin and Paclitaxel compared to established TSCC cell lines."
• NEWJul Association Between Individualized Estimated Glomerular Filtration Rate and Cumulative Cisplatin Dose in Head and Neck Cancer. (Anticancer research, 2026, PMID 42373265): "achieving a cumulative cisplatin dose of ≥200 mg/m2 is associated with improved outcomes."
• NEWJul Efficacy of Hypotonic Cisplatin Treatment After Marginal Resection of Fibrosarcoma: A Preliminary Report. (Anticancer research, 2026, PMID 42373275): "The aim of this study was to validate the efficacy of hypotonic cisplatin treatment after marginal resection."
• NEWJul Balloon-occluded Alternative Infusion of Fragmented Gelatin Particles of TACE for Hepatocellular Carcinoma Refractory to Atezolizumab-Bevacizumab. (Anticancer research, 2026, PMID 42373279): "This study aimed to verify the efficacy and safety of balloon-occluded alternative infusion of cisplatin solution and gelatin particles of transarterial chemoembolization (BOAI-TACE) for hepatocellular carcinoma (HCC) refractory or intolerant to atezolizumab plus bevacizumab combination therapy."
• NEWJun Electroporation as a strategy to improve the efficacy of chemotherapy in neuroblastoma: an in vitro study. (Radiology and oncology, 2026, PMID 42359758): "We investigated the efficacy of electroporation and cisplatin as a treatment for neuroblastoma in vitro, and explored whether inhibition of DNA repair mechanisms with olaparib potentiates its effects."
• NEWJun Downregulation of SLC44A4 in nasopharyngeal carcinoma is associated with malignant progression, B-cell/TLS-related immune features, and sensitivity to DNA-damaging agents. (PloS one, 2026, PMID 42361082): "SLC44A4 overexpression also increased sensitivity to DNA-damaging agents, including temozolomide, doxorubicin, cisplatin, olaparib, and etoposide, while decreasing sensitivity to 5-fluorouracil."
• NEWJun Real-World Survival and Toxicity Outcomes of Fluorouracil With vs. Without Leucovorin in Metastatic Colorectal Cancer. (Journal of gastrointestinal cancer, 2026, PMID 42329513): "Fluorouracil (5-FU) remains a cornerstone of systemic therapy for metastatic colorectal cancer (mCRC)."
• NEWJun DLL1-mediated ferroptosis resistance via the Notch-Nrf2/GPX4 axis drives cisplatin resistance in ovarian cancer. (Cancer & metabolism, 2026, PMID 42310697): "cisplatin resistance being a major clinical challenge."
• NEWJun Depleting S100A4 in Cancer-Associated Fibroblasts Reverses Cisplatin Resistance in Esophageal Cancer. (ACS applied bio materials, 2026, PMID 42313741): "Cisplatin is a first-line chemotherapeutic drug for the treatment of esophageal cancer."
• NEWJun Heteronemin suppresses chemoresistant oral squamous cell carcinoma cells through ROS-mediated apoptosis and cuproptosis-associated mitochondrial stress. (Apoptosis : an international journal on programmed cell death, 2026, PMID 42315805): "HET dose- and time-dependently reduced SAS-CR viability, inhibited clonogenic growth, and exhibited stronger cytotoxicity than cisplatin or 5-fluorouracil."