Promoting apoptosis as a strategy for cancer drug discovery

Top Cited Papers
Publisher Website
Google Scholar
Abstract
In many cancers, the normal process for eliminating unwanted cells (apoptosis) is deregulated. The deregulation of apoptosis leads to the unchecked growth of tumours and the development of resistance to chemotherapy. Drugs that restore apoptosis might selectively kill cancer cells that have triggered a death signal and have become dependent on the deregulation of apoptosis pathways. Agonistic antibodies against the tumour-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors and a soluble, truncated TRAIL ligand are in phase I/II clinical trials for the treatment of cancer. BCL2 antisense oligonucleotides are in phase III clinical trials and pre-registration, and small-molecule BCL2-family inhibitors are in early phase I clinical trials and in late preclinical discovery for the treatment of chronic lymphocytic leukaemia and solid tumours. IAP (inhibitor of apoptosis) protein inhibitors, MDM2 antagonists and other apoptosis-inducing compounds are under preclinical examination for possible use in cancer therapy. For these compounds to succeed, it will be important to test them in well-designed clinical trials to determine the cancer patients that are most likely to respond to the particular agent, the optimum dose and schedule, and the best combination with other drugs.