BJA/RCoA International Collaborative Grants

Mater University Hospital, University College Dublin
Imperial College, London

Title
Can perioperative anaesthetic-analgesic techniques during cancer surgery influence cancer outcome? Next steps in further defining its biological plausibility of this hypothesis in vitro and vivo

Amount
£99,992

Scientific Abstract
Addressing the hypothesis that anaesthetic-analgesic technique during cancer surgery might influence long term recurrence or metastasis has become a research priority. Experimental data from cell cultures suggests that amide local anaesthetics, prototype lidocaine, have multiple cellular effects which inhibit metastasis and enhance sensitivity to chemotherapy. Propofol and high dose steroids have also been hypothesised to interact with the immune system, inhibit the surgical stress response and enhance recovery, but cellular mechanisms remain to be elucidated. Further, there is a dearth of in vivo and translational clinical data, an essential bridge to convincing grant awarding organisations to fund the necessary prospective, randomised controlled clinical trials.

We propose a collaborative programme delivering in vivo experiments, using the 4T1 mouse model, which will yield novel data on the effect of perioperative lidocaine, propofol and steroids on chemotherapy treated tumour metastasis post-surgery. Simultaneously, we will undertake a small clinical trial, investigating the effect of plasma and breast cancer tissue collected from patients who were randomised to an ongoing clinical trial investigating two distinct anaesthetic techniques in long term cancer outcome. Plasma from these patients will be exposed to breast cancer cells in vitro to determine its effect on expression of 80 genes associated with increased metastasis risk.

Weill Cornell Medicine, USA
Birkbeck College, University of London

Title
General anaesthetic interactions with full-length voltage-gated sodium channel NavMs

Amount
£99,848

Scientific Abstract
General anaesthetics have evolved to become a vital part of modern medicine allowing performance of complex and invasive medical procedures. Despite their widespread clinical use, the molecular mechanisms by which they induce anaesthesia are mostly unknown. Volatile anaesthetics can inhibit voltage-gated sodium channels, which are crucial for initiating and propagating action potentials in excitable cells (Herold and Hemmings, 2012). Volatile anaesthetics alter sodium channel function by reducing peak Na⁺ current and stabilizing the inactivated conformational state resulting in reduced Na⁺ flow through the channel pore.

The mechanisms by which the modern volatile anaesthetics desflurane and sevoflurane interact with sodium channels are unclear. We propose to address this question using a synergistic structural and functional approach. The prokaryotic sodium channel NavMs provides an excellent model for studying drug interactions with human sodium channels (Bagnéris et al., 2014; Sula et al., 2017). We will obtain structural information using circular dichroism spectroscopy to compare with functional information obtained using patch-clamp electrophysiology. This combined approach will improve our fundamental understanding of anaesthetic interactions with sodium channels, which will guide development of newer anaesthetics with fewer harmful side effects to improve patient safety.