Despite the many side effects of Thalidomide, (e.g. phocomelia and peripheral neuropathy), the drug is still used for the treatment of multiple myeloma (MM) and several other debilitating conditions. Regardless of the strict controls on Thalidomide use and distribution, several babies with Thalidomide embryopathy have been born in the last two decades. Most of these babies were from Brazil and Africa, where the drug is administered for leprosy treatment. I have been working with several structural analogs of Thalidomide to identify non or reduced teratogenic versions, negating the risk of embryonic exposure. I have developed several embryological models to screen compounds for inflammatory and teratogenic properties. I have shown Pomalidomide (an established Thalidomide analog), at potently anti-inflammatory doses, is non-anti-angiogenic, non-teratogenic and non-neurotoxic. This contrasts with Lenalidomide (a Thalidomide analog in clinical use for MM with reportedly reduced side-effects), which I have shown to be anti-angiogenic, teratogenic and neurotoxic. Furthermore, I have uncovered molecular differences between Lenalidomide and Pomalidomide that facilitates their different effects. I have also characterised the teratogenic properties of two potent anti-cancer drugs. This has allowed me to compare and contrast their functions with other Thalidomide analogs and shed further light on potential molecular targets of Thalidomide. Finally, one of the outstanding questions to be resolved in Thalidomide embryopathy is how the drug causes phocomelia (loss of proximal elements). I have examined this by using classical limb embryology transplantation techniques to experimentally induce phocomelia and analyse the cell biology underlying this defect. I have correlated changes in the signalling environment to the origins of phocomelia. I further show that phocomelia arises slightly later in development than previously thought.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:577662 |
| Date | January 2013 |
| Creators | Mahony, Chris |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=201698 |
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