Fennell, Dean A.; (2000) Novel pharmacological strategies for antagonizing anti-apoptosis protein function in malignancy. Doctoral thesis (Ph.D.), University College London.

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Abstract

Historically, cytotoxic therapies have provided the greatest advances in the treatment of malignant disease. Although some cancers are curable, many are not. Chemotherapeutic drugs rely upon the induction of a phylogenically old, cell suicide programme termed apoptosis for their efficacy. Apoptotic sensitivity is associated with curability, whereas, intrinsic resistance plays a major role in limiting therapeutic effectiveness. Mitochondria, the centres for aerobic respiration in the cell also play a pivotal role in regulating apoptosis. The anti-death proteins Bcl-2 and Bc1-XL localize to the outer mitochondrial membrane, and are expressed at high levels in many resistant malignacies compared with normal tissues. These proteins contribute to resistance by blocking apoptosis, and therefore represent valid targets for the development of novel inhibitory strategies. This thesis presents two strategies with therapeutic potential for antagonizing the anti-death action of Bcl-2 and Bc1-XL in haematological and epithelial malignancies. The first, involves the suppression of Bcl-2 and Bc1-XL gene expression by antisense oligodeoxynucleotides in vitro and in vivo. Mathematical models of antisense pharmacology are presented. The second, targets the mitochondrial megachannel that is intimately involved in apoptosis, and is regulated by binding to Bcl-2 and Bc1-XL In order to quantitatively measure the putative apoptosis sensitizing efficacy of these approaches at single cell resolution, stochastic models are described, enabling robust estimation of the distribution of tolerances and latency preceding apoptosis. The peripheral benzodiazepine receptor interacts with the mitochondrial megachannel. Evidence is provided, that Bcl-2 resistant apoptosis sensitization is mediated in vitro, in vivo, and ex vivo, by the ligand PK11195, through a mechanism involving direct megachannel regulation. This occurs not via the peripheral benzodiazepine receptor as previously thought, but through de novo generation of reactive oxygen species. Investigations of PK11195 pharmacodynamics, and molecular structural studies using proton nuclear magnetic resonance spectroscopy support a novel mechanism of action.

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