Streptozotocin revisited: Pharmacological determinants supporting new scheduling strategies in neuroendocrine tumours

Streptozotocin (STZ) remains a potentially effective chemotherapeutic agent for pancreatic neuroendocrine tumours, more than five decades after its initial use. Despite its longstanding clinical application, STZ dosing regimens have traditionally been driven by empirical practice rather than by pharmacokinetic or pharmacodynamic rationale. Recent advances in understanding its molecular mechanism of action, selective uptake via the glucose transporter type 2 transporter, and DNA-methylating properties provide a solid foundation for revisiting its therapeutic role and optimising its scheduling. This review outlines the key pharmacological features of STZ, including its rapid systemic clearance, narrow volume of distribution, and renal elimination, all of which support the use of short intravenous infusions and fractionated schedules to minimise nephrotoxicity while maintaining efficacy. Comparative insights with temozolomide highlight the unique delivery and tissue tropism advantages of STZ, particularly in pancreatic neuroendocrine tumours. In addition, emerging biomarkers, such as O⁶-methylguanine-DNA methyltransferase deficiency and mismatch repair status, may help refine patient selection for STZ-based chemotherapy. Clinical data from classical and modern regimens, such as those combining STZ with 5-fluorouracil or capecitabine, suggest sustained disease control in well-selected patients. The potential for biomarker-guided strategies and pharmacology-informed protocols supports a contemporary repositioning of STZ in neuroendocrine oncology. Rational redesign of dosing, improved toxicity management, and integration with personalised medicine may revitalise the clinical utility of this historically valuable agent.