Herceptin Research Today is a free monthly online journal that collates and summarizes the latest research about Herceptin, including details on side-effects, breast cancer, treatment, therapy. | ||||||||
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Bs24 apoptosis: why surgeons need to understand it.Bundred NJ University Hospital of South Manchester, Manchester, United Kingdom. Apoptosis (programmed cell death) is a mechanism which enables regulation of cell number in tissues and elimination of unneeded, ageing or damaged cells. Imbalances between epithelial proliferation and apoptosis contributes tumour genesis and tumour progression. Apoptosis is morphologically characterised by nuclear condensation and cytoplasmic shrinkage. The process of proliferation and apoptosis within tumours is closely linked with higher proliferative accounts being associated with higher apoptotic rates. Initial therapeutic advances involved agents that block proliferation but evidence is mounting that it is blocks to apoptosis which need to be overcome to enhance treatments for breast cancer. A newer group of novel biological agents such as the HER2 inhibitors trigger apoptosis to achieve responses. Apoptosis occurs via two predominant pathways, which act via a Caspase effector mechanism. An extrinsic pathway activated by ligands to the TRAIL, FAS/TNF family of cell membrane bound death receptors which recruits intracellular adaptor proteins including pro-Caspases to induce apoptosis in the cells. Recent studies suggest Caspase 8 alterations influence breast cancer development via the extrinsic pathway. The intrinsic pathway starts from the mitochondria and can be activated by a large number of signals including irradiation, DNA damage and alteration of the ratio of BCL2, BAX family members. This leads to release of Cytochrome C and activation of Caspase 9 leading to apoptosis. Apoptosis and activation of Caspase 9 can be prevented by the Inhibitor of Apoptosis Protein (IAP) family. Breast cancers often express mutated p53 which makes them resistant to apoptosis induced by alkylating agent chemotherapy. Pro-apoptotic agents will potentially improve the effectiveness of chemotherapy. Breast cancer expresses the BCL2 family proteins which are induced by oestrogen and thus anti-oestrogens such as Tamoxifen and Fulvestrant can induce apoptosis by increasing BAX expression and decreasing BCL2 activity. Newer agents such as Herceptin, Lapatinib (dual molecular HER1/HER2 inhibitor) and the RAS farnesylation transferase inhibitors induce apoptosis by activating the pro-apoptotic protein BAD another member of the BCL2 family. Combinations of drugs which induce apoptosis can potentially be used to cause tumour regression. For instance, a one per cent increase in apoptosis is likely to have the same effect as a 50% reduction in cell proliferation on tumour growth. Current targets for drug discovery includes targets against endogenous antagonists of Caspase activation and IAP antagonists. Therapies for inducing apoptosis will be discussed. Published 10 May 2007 in ANZ J Surg, 77: A6.
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