Cell death and cancer: replacement of apoptotic genes and inactivation of death suppressor genes in therapy

This review provides a critical evaluation of the increasing use of gene therapy in the treatment of malignancies to induce active cell death (ACD, apoptosis). This approach is consistent with the notion that cancer is an anomalous accumulation of cells largely resulting from diminished cell death. The review details the main genes potentially useful for therapy. Among these, p53 has received the majority of the investigators' attention and provided encouraging results. Even greater hope is offered by newly tried direct inducers of apoptosis, such as bax, bclX(s) and caspases. Another fruitful direction is the association of apoptosis-inducing gene transfer with radio- and chemotherapy, which are also inducers of ACD. There is a delicate balance between cell gain through mitosis and cell loss in neoplasia because spontaneous apoptosis is widely present in tumors. In fact, the tumor environment favors bystander cell killing which appears to be a fundamental mechanism isofar as the rate of observed cell mortality cannot be accounted for by the known methods of gene transduction with efficiencies far below 100%. We conclude that apoptosis offers a mainstream approach for cancer gene therapy since ACD is highly inducible and only limited gains in malignant cell apoptosis may displace tumors from growth to regression.