Stojanovska, Vanesa (2017) Potential Mechanisms Underlying Oxaliplatin-Induced Enteric Neuropathy. PhD thesis, Victoria University.

Abstract

Cisplatin, carboplatin and oxaliplatin are platinum-based agents that are amongst the most widely used drugs for the treatment of cancer in the clinical setting. Despite their therapeutic efficacy, these platinum-based drugs are associated with a myriad of dose-limiting side-effects. These include acute and chronic peripheral neuropathies (paraesthesias, dysaesthesias), and gastrointestinal complications (nausea, vomiting, constipation and diarrhoea). These side-effects decrease quality of life and cause life-threatening cardiac and renal sequeale consequent to malnutrition, dehydration and fluid and electrolyte imbalances, which in severe cases, can lead to death. Extensive research into the mechanisms underlying chronic peripheral neuropathies associated with platinum-based agents has focused on drug accumulation within the dorsal root ganglia (DRG). Only recently, a few studies have demonstrated damage to the enteric nervous system (ENS) following platinum-based chemotherapy. The ENS is an intrinsic and complex orchestration of nerves embedded throughout the entirety of the gastrointestinal tract innervating the musculature and mucosa. The mechanisms underlying ENS toxicity remain unknown. Furthermore, the gastrointestinal tract receives extrinsic innervations and it is also unknown if these nerves are vulnerable to platinum-based drugs. Platinum-based drugs mediate their cytotoxic effects through the formation of interstrand and intrastrand DNA adducts, particularly binding to the N7 position of guanine nucleotides. Essentially, these platinum lesions inhibit DNA replication through the distortion of the helical structure. DNA damage typically results in the induction of canonical apoptotic cascades. Until recent years apoptosis was deemed an immunologically ‘silent’ or ‘tolerogenic’ event. However, unlike cisplatin and carboplatin, there is substantial evidence shown in models of cancer that oxaliplatin prompts a fatal immune response against cells committed to apoptosis. This phenomenon is termed ‘immunogenic cell death’. Oxaliplatin-induced cytotoxicity results in the hallmark presentation of damage-associated molecular patterns (DAMPs) which can be recognised by antigen-presenting cells, and thus, stimulating phagocytosis of apoptotic cells and/or debris. The gastrointestinal tract harbours ~70% of the body’s immune system, and so it is unknown whether oxaliplatin treatment can induce changes in immunological responses which may directly or inadvertently induce ENS damage. Given the bi-directional communication between the immune and nervous systems, exploring the consequences of oxaliplatin-induced cytotoxicity and potential immunogenicity may provide insight into the multifaceted mechanisms underlying neuronal damage and death which impact gastrointestinal function.

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