Investigations into Pyrrolo-1,5-Benzoxazepine-15-induced apoptosis of chronic B-cell malignancies

Abstract

Multiple myeloma and chronic lymphocytic leukaemia (CLL) are chronic B-cell malignancies, which are characterised by the accumulation of malignant cells with low proliferative capacity and defective apoptotic mechanisms. Although considerable advances in the treatment of these diseases have been achieved in recent years, most notably the development of the proteasome inhibitor Bortezomib as an anti-myeloma agent, these malignancies remain incurable. In addition, a major drawback to the use of existing chemotherapeutic drugs is the eventual development of resistance. Thus, there is an urgent need for the development of novel agents which may provide alternative treatment options for this group of patients. Pyrrolo-1,5-benzoxazepines (PBOX) are a series of novel microtubule targeting agents (MTA) which have demonstrated anti-cancer activity against a variety of cancer cell types. Importantly, PBOX compounds display minimal toxicity against normal blood and bone marrow cells. In this thesis, PBOX-15, a potent member of the PBOX series, is proposed as a potential novel agent for the treatment of myeloma and CLL, and evaluation of its mechanism of action is performed.