Defects in programmed cell death (apoptosis) mechanisms play important roles in tumor pathogenesis, allowing neoplastic cells to survive beyond their normally intended lifespans, subverting the need for exogenous survival factors, providing protection from hypoxia and oxidative stress as tumor mass expands, and allowing time for accumulative genetic alterations that deregulate cell proliferation, interfere with differentiation, promote angiogenesis, and increase cell motility and invasiveness during tumor progression (Reed, 1999). In fact, apoptosis defects are recognized as an important complement to protooncogene activation, as many deregulated oncoproteins that drive cell division also trigger apoptosis (eg, Myc, E1a, Cyclin-D1)(Green and Evan, 2002). Similarly, defects in DNA repair and chromosome segregation normally trigger cell suicide as a defense mechanism for eradicating genetically unstable cells, and thus apoptosis defects permit survival of genetically unstable cells, providing opportunities for selection of progressively aggressive clones (Ionov et al., 2000). Apoptosis defects also facilitate metastasis by allowing epithelial cells to survive in a suspended state, without attachment to extracellular matrix (Frisch and Screaton, 2001). They also promote resistance to the immune system, inasmuch as many of the weapons cytolytic T cells (CTLs) and natural killer (NK) cells use for attacking tumors depend on integrity of the apoptosis machinery (Tschopp et al., 1999). Finally, cancer-associated defects in apoptosis play a role in chemoresistance and radioresistance, increasing the threshold for cell death and thereby requiring higher doses for tumor killing (Makin and Hickman, 2000). Thus, defective apoptosis regulation is a fundamental aspect of the biology of cancer.

When it comes to the successful eradication of cancer cells by nonsurgical means, ultimately, all roads lead to apoptosis. Essentially all cytotoxic anticancer drugs currently in clinical use, when they work, induce apoptosis of malignant cells. While microtubule binding drugs, DNA-damaging agents, and nucleosides are important weapons in the treatment of cancer, a new class of targeted therapeutics may soon be forthcoming based on strategies that have emerged from a deeper understanding of the molecular mechanisms that underlie the phenomenon of apoptosis. Apoptosis is caused by proteases known as “caspases,” for cysteine aspartyl-specific proteases (Cryns and Yuan, 1999; Thornberry and Lazebnik, 1998). Caspases constitute a family of intracellular cysteine proteases (n= 11 in humans), which collaborate in proteolytic cascades where caspases activate themselves and each other. Within these proteolytic cascades, caspases can be positioned as either upstream “initiators” or downstream “effectors” of apoptosis. Several pathways for activating caspases exist (Figure 1). First, of the? 30 members of the tumor necrosis factor (TNF)-family receptors, eight contain a so-called death domain (DD) in their cytosolic tail (Locksley et al., 2001). Several of these DD-containing TNF-family receptors