Anticancer Drugs Can Induce Apoptosis

Studies performed over the past 15 years have demonstrated that virtually all the agents currently utilized to treat cancer can induce apoptosis (1), a morphologically and biochemically distinct cell death process (2), in susceptible cells. Morphologically, this process is characterized by plasma membrane blebbing, cell shrinkage, and chromatin condensation followed by disassembly of the cell into multiple membrane-enclosed fragments, which are then engulfed by neighboring cells or professional phagocytes (2).

From: Cancer Drug Discovery and Development Apoptosis, Senescence, and Cancer Edited by: D. A. Gewirtz, S. E. Holt and S. Grant © Humana Press Inc., Totowa, NJ

These morphological changes are thought to reflect, at least in part, the action of caspases, unique intracellular proteases that digest polypeptides required for cellular integrity and survival (3-5).

Additional analyses have suggested that apoptosis also occurs after administration of antileukemic therapy in the clinical setting (6-10) and after treatment of solid tumors in certain animal models (2,11,12). These observations, which suggest that proximal effects of divers anticancer drugs can lead to activation of a common final death pathway, have prompted many investigators to speculate that alterations in the apoptotic machinery or its regulation might lead to a form of broad-spectrum drug resistance (13-17). It is important to emphasize, however, that cells can also suffer other fates, including senescence (see Chaps. 11 and 19) and so-called mitotic catastrophe (see Chap. 4), after exposure to chemotherapeutic agents (18-20). These alternative outcomes need to be considered in determining the overall response of tumor cells to antineoplastic agents (20).

This chapter describes apoptosis as an endpoint of anticancer drug exposure. In the sections that follow, current understanding of the apoptotic machinery, particularly the intrinsic pathway of apoptosis, is summarized. In addition, cancer-associated alterations of this pathway are described, and evidence suggesting that these alterations might contribute to drug resistance is discussed.

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