BJA/RCoA PhD Studentship
Antioxidant protection in mitochondria in chemotherapyinduced neuropathic pain
Professor Helen Galley
What is known already:
Certain types of cancer are treated effectively by a drug called paclitaxel. However, some people treated with this drug develop a very unpleasant side effect called neuropathy, which results in burning sensations, tingling, numbness and pain. In some patients the drug treatment has to be stopped. It is thought that this side effect occurs as result of damage inside nerve cells- in the mitochondria- by toxic chemicals called free radicals. Under normal conditions antioxidants protect against this damage.
However, ordinary antioxidants cannot get into the mitochondria and so modified antioxidants have been developed, which can get inside mitochondria and directly protect against free radical damage where it is most needed. We have shown previously that these modified antioxidants are very good at protecting against free radical damage to mitochondria in other diseases.
Aim of the proposed study:
We have already shown in experiments in nerve cells in the laboratory that the modified antioxidants can protect against damage to mitochondria caused by paclitaxel. The aim of the proposed study is to see if these modified antioxidants can also protect against the side effects of paclitaxel treatment. We also propose to try and identify if there are measurements of damage to mitochondria we can use to predict which patients treated with paclitaxel will go on to get the side effect of neuropathy.
Proposed methods:
Before we can try the modified antioxidants in patients we need to try them in rats first. If rats are injected with paclitaxel they develop symptoms similar to the neuropathy seen in patients. We propose to give modified antioxidants to rats in their drinking water for two weeks, then inject them daily with paclitaxel. Their behaviour in response to heat and cold, or touching their feet with a thin flexible wire, can be used to assess the effect of the antioxidant treatment. We will compare the responses of rats treated with the modified antioxidants with rats treated with non-modified antioxidants. We will also take blood from patients beginning treatment with paclitaxel and measure damage to mitochondria. We can then try and relate any damage to subsequent neuropathy symptoms. In the future we may be able to predict which patients will develop neuropathy. If the antioxidant treatment is successful in rats we can then go on to try the treatment in patients and having a marker to identify patients who will benefit, or to monitor their progress, will be useful. The modified antioxidants have already been safely used in patients with other diseases and so we hope that if they work in rats, it will be relatively straightforward to try them in patients being treated with paclitaxel. If the antioxidants can prevent or alleviate neuropathy, there will be fewer patients in whom paclitaxel treatment has to be stopped.
Characterisation of fentanyl based bivalent opioids
Professor David Lambert
Background:
Up to 90% of cancer patients experience pain in the final year of their lives and this is a big problem. Current painkilling drugs like morphine also produce side effects, such as
depressed breathing, drowsiness, constipation and tolerance. Tolerance is an important problem where a drug, like morphine, becomes less effective the longer it is used. Tolerance usually results in prescribing increased doses and hence more side effects and a vicious circle with the patient at the centre results. Traditional opioid based pain-killers are particularly prone to development of tolerance and many groups have tried to design new morphine like drugs with reduced side effects. This has been relatively unsuccessful. In the laboratory, in simple cell-based systems, a tolerance-like response called desensitization can be easily measured. Opioids produce their effects by targeting a particular group of receptors (locks for which morphine is the key) and there are three important types for this project; MOP, DOP and NOP. Traditional pain-killers unlock or activate MOP but recently there has been a lot of interest in interactions between members of this group of locks. Indeed, shutting either DOP or NOP while opening MOP with morphine (in rats) produces pain relief with much less tolerance. This interaction is an area where progress can be made.
Aims:
We plan to use very new chemical technology to make a single drug that can open the MOP lock whilst simultaneously closing the DOP or NOP lock simultaneously. We will evaluate these in the test tube with a view to eventual progress to human clinical trials. This project will form a collaborative (with USA and Italy) 3year PhD studentship for a laboratory scientist who will eventually add to the declining pool of researchers engaged in pain related research.
Methodology:
In this laboratory study we will use opioid receptor building blocks to make simple systems to test our new drugs. We will measure how they interact (bind) with each individual receptor then look for differences when we make systems more like the brain; where more than one receptor is present. We will then treat these simple systems with our new drugs and the existing ones like morphine and fentanyl for long periods of time and examine how the receptors behave in producing a response; we will look for differences in desensitisation.
Expected outcomes:
We predict that our new drugs acting at multiple targets will be superior to either morphine or fentanyl; that is they will bind to the individual receptors and produce desensitisation at MOP receptor but when DOP or NOP is present this desensitisation will be markedly reduced or even absent. We hope the data gathered during this project will enable us to apply for larger grants to expand the types of molecules we design and test.
Implications:
This work offers the potential of a completely new approach to management of pain for patients with cancer and we hope that our work will lead to the acceptance of a new class of pain-killers.
