Identification and characterization of novel compounds for the selective induction of apoptosis in malignant cells.
Published: 2005
Language: eng
Number of pages: 182
Description: The need for novel therapeutic agents which selectively harm tumour cells of hematopoietic origin whilst leaving normal cells unharmed is urgently required. In particular, agents that induce tumour cells to undergo apoptosis will lead to the full eradication of the tumour without triggering an inflammatory response. Two different resources for chemical compounds were used to identify novel apoptosic agents for anti-cancer use: synthetic derivatives of a naturally occurring disulfide and the statin family, currently in use to control hypercholesterolemia. Mechanistic studies were conducted to determine the most effective manner in which to use these novel compounds in the clinic.The fungal derivatives of the statin family have been shown to induce apoptosis in a subset of tumours without reducing the proliferative potential of myeloid progenitors. We determined that of the synthetic statins, cerivastatin was the most potent inducer of apoptosis in acute myelogenous leukemic cells yet still retained specificity towards tumour cells. Our studies show that sensitivity to statin-induced apoptosis correlates with multiple myeloma cells harbouring a translocation of fibroblast growth factor receptor 3 (FGFR3) and an activating mutation of either FGFR3 or Ras. Mechanistic studies reveal that the down-regulation of anti-apoptotic Bcl family members and phospho-ERK contributes to but is not essential for statin-induced apoptosis. In addition, the loss of not one but multiple prenylated proteins may be responsible for statin-induced apoptosis.We assayed synthetic relatives of a naturally occurring disulfide, dysoxysulfone, which are known to have medicinal properties. While disulfides are known to be general cytotoxics, our study shows that tumour specificity can be achieved by altering the functional groups flanking the disulfide. Biological activity and specificity was determined through a functional screen in which the compounds were assayed against both malignant and non-transformed cell lines. By this approach, seven compounds were identified to selectively induce apoptosis. Initial mechanistic studies reveal that these lead compounds may induce apoptosis in two separate manners.Thus, our work shows two promising avenues to pursue for the development of tumour-specific apoptotic agents in the elimination of hematopoietic malignancies. Further mechanistic analysis of these compounds will maximize the potential of these compounds in the clinic.
Notes: Thesis (Ph.D.)--University of Toronto, 2005.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 66-06, Section: B, page: 3074.