TRAIL modulators

Specific induction of apoptosis is an interesting therapeutic strategy for destroying tumor cells. Tumor necrosis factor (TNF)-related, apoptosis-inducing ligand (TRAIL or Apo2L) is an attractive candidate in this respect, as it induces apoptosis in a wide range of tumor cells and xenografts, without causing toxicity to normal cells (1). Other recombinant members of the TNF family-that is, Fasligand (FasL) and TNF-also induce apoptosis of cancer cells in preclinical models, but have failed to attain broad application in cancer treatment due to their side effects. Administration of FasL in preclinical studies induced severe liver toxicity, hampering its introduction in the clinic (2). TNF is only administered by isolated limb perfusion to achieve limb salvage in soft tissue sarcoma or melanoma, because systemic use of this agent, if not employed at very low doses, induces a sepsis-like syndrome (3,4). Recombinant human (rh) TRAIL and agonistic monoclonal antibodies that target the TRAIL pathway appear to have a more favorable safety profile and are currently in early clinical development. In this chapter we describe the TRAIL pathway, the factors involved in modulating this route, the physiologic role of TRAIL, and the therapeutic possibilities of targeting this pathway in oncology.