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 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 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.

Recent Publications Summary

Recent publications on cisplatin/fluorouracil focused mainly on its role in combination chemotherapy and on factors that may influence response or tolerability. In head and neck cancer, one study examined the relationship between individualized glomerular filtration rate and the ability to reach a cumulative cisplatin dose of at least 200 mg/m2 during concurrent chemoradiotherapy, reflecting the importance of renal function in maintaining cisplatin-based treatment intensity 42373265Jun. In biliary tract cancer, another multicenter real-world study evaluated aprepitant as prophylaxis for chemotherapy-induced nausea and vomiting during gemcitabine plus cisplatin therapy, highlighting supportive care considerations for cisplatin-containing regimens 42203357May.

Several studies explored mechanisms of cisplatin sensitivity or resistance in tumor models. In esophageal cancer, cancer-associated fibroblasts from cisplatin-resistant patients showed elevated S100A4, and a targeted CREKA-lipid@Fe-siS100A4 system reversed cisplatin resistance in vitro and in vivo 42313741Jun. In ovarian cancer, DLL1 was linked to cisplatin resistance through ferroptosis resistance via the Notch-Nrf2/GPx4 axis 42310697Jun. In oral cancer, santamarine synergized with cisplatin to suppress cell viability, migration, and colony formation while increasing reactive oxygen species, DNA damage, and apoptosis through JNK signaling 42187533May. dexmedetomidine also enhanced cisplatin chemosensitivity in resistant esophageal carcinoma cells by promoting pyroptosis through the SREBF1/miR-185-5p/Caspase-1 axis, with increased Caspase-1, GSDMD-N, IL-1β, and IL-18 41966778Apr.

Other publications examined cisplatin in experimental treatment settings or as a comparator. Electroporation was tested as a strategy to improve cisplatin efficacy in neuroblastoma in vitro, with the study also assessing whether olaparib could further potentiate the effect 42359758Jun. Hypotonic cisplatin treatment after marginal resection was preliminarily evaluated in fibrosarcoma as a local approach after non-radical surgery 42373275Jun. In hepatocellular carcinoma refractory or intolerant to atezolizumab plus bevacizumab, balloon-occluded alternative infusion of cisplatin solution and gelatin particles of transarterial chemoembolization was investigated for efficacy and safety 42373279Jun. In oral squamous cell carcinoma, heteronemin was reported to be more cytotoxic than cisplatin or fluorouracil in chemoresistant cells, underscoring the continued use of cisplatin and fluorouracil as reference agents in drug-response studies 42315805Jun.

A separate patient-derived tongue squamous cell carcinoma model study established new non-smoking, treatment-naïve cell lines for 3D and in vivo drug-response work, including evaluation against cisplatin and fluorouracil 42371352Jun. In nasopharyngeal carcinoma, SLC44A4 overexpression increased sensitivity to cisplatin while decreasing sensitivity to fluorouracil, suggesting divergent effects on DNA-damaging agents versus fluorouracil in this disease context 42361082Jun.

What Changes, What Holds

1. Renal function now looks like a practical limiter of cisplatin intensity in CF-based treatment
REINFORCES The new work sharpens the baseline’s toxicity account by showing that kidney function can determine whether patients actually reach a commonly used cumulative cisplatin exposure during concurrent chemoradiotherapy 42373265Jun. It does not change what CF is, but it strengthens the case that nephrotoxicity is not just a side effect to monitor after the fact; it can directly constrain deliverable dose and therefore regimen effectiveness.

2. Resistance biology remains a major reason CF needs adjuncts, but the specific escape routes are more diverse than the baseline implies
REINFORCES These studies do not overturn cisplatin’s established role; they extend the resistance problem by identifying additional tumor- and microenvironment-linked mechanisms that blunt response and by showing that targeted or pharmacologic add-ons can restore sensitivity in preclinical systems 42313741Jun41966778Apr. The practical implication is that CF resistance is not a single phenomenon and may require mechanism-matched combinations rather than one-size-fits-all escalation.

3. cisplatin is still being tested as a comparator and local therapy, not displaced as a reference standard
REINFORCES The new reports mainly show that cisplatin continues to anchor experimental treatment design, whether as a benchmark for novel agents or as a component of exploratory delivery strategies 42359758Jun42373279Jun. That leaves the baseline intact: these are not new clinical roles that replace CF, but additional ways investigators are probing how far cisplatin-based cytotoxicity can be pushed in difficult settings.

4. fluorouracil sensitivity may diverge from cisplatin sensitivity in some tumors, so CF cannot be assumed to behave as a single response unit
NEW DIRECTION The nasopharyngeal carcinoma finding goes beyond the baseline’s broad statement that CF is a backbone regimen by showing that a biomarker can increase sensitivity to cisplatin while reducing sensitivity to fluorouracil 42361082Jun. That does not contradict CF’s established use, but it does mean the two drugs may separate biologically in ways that matter for prediction and personalization.