Disulfiram + Cisplatin

The combination of disulfiram and cisplatin is being investigated as a potential treatment for various cancers, particularly in cases where cisplatin resistance has developed. Disulfiram is an FDA-approved drug originally used to treat alcohol addiction, while cisplatin is a well-established chemotherapy agent. ## Mechanism of Action The combination works through several mechanisms: 1. Disulfiram acts as an aldehyde dehydrogenase (ALDH) inhibitor, which may help restore sensitivity to cisplatin in resistant tumors[1][4]. 2. The combination has shown synergistic cytotoxic effects in preclinical studies, enhancing tumor cell death beyond what either drug achieves alone[5]. 3. Both drugs independently induce ATF3 (Activating Transcription Factor 3) protein expression, and their combination enhances this effect, which may contribute to their synergistic cytotoxicity[5]. ## Clinical Studies A Phase II study conducted from May 2019 to September 2021 evaluated this combination in patients with multiple relapsed/refractory germ cell tumors (GCTs)[1][4]. The study administered: - Disulfiram: 400 mg daily until progression or unacceptable toxicity - Cisplatin: 50 mg/m² on days 1 and 2, every 3 weeks Unfortunately, this study failed to achieve its primary endpoint, suggesting limited efficacy in restoring cisplatin sensitivity in heavily pretreated GCT patients[1][4]. None of the 12 enrolled patients achieved objective response, and the study was terminated at its first stage. The median progression-free survival was only 1.4 months, and median overall survival was 2.9 months. Another ongoing clinical trial is investigating cisplatin combined with disulfiram for advanced gastric cancer[6]. In this study: - Control group: Cisplatin 80 mg/m² intravenous drip on day 1, with 21 days as one treatment course, for six courses - Observation group: Same cisplatin regimen plus disulfiram 400 mg orally daily until the end of chemotherapy ## Safety Profile The combination treatment was generally well-tolerated in the GCT study, though several grade 3/4 adverse events were reported[1][4]: - Fatigue (41.7% of patients) - Thrombocytopenia (33.3%) - Anemia (25.0%) - Neutropenia, nausea, and infection (16.7% each) ## Preclinical Evidence Laboratory studies have shown promising results for this combination in various cancer types: - Enhanced cytotoxicity in small cell lung cancer cells[3] - Synergistic inhibition of cell proliferation in embryonal carcinoma cells[7] The combination appears to work through multiple mechanisms, including ALDH inhibition and enhanced ATF3 expression, which may contribute to overcoming cisplatin resistance in certain cancer types.