Gene Therapy for Killing p53-Negative Cancer Cells: Use of Replicating Versus Nonreplicating Agents

Abstract

Research has focused on the use of viral vectors to attack p53-negative cancer cells. Such agents may be nonreplicating, whereas others are replicating. This paper uses mathematical models to study the conditions under which therapy can lead to tumor remission. It is found that the optimal characteristics of the vector can be quite different depending on whether the virus replicates or not. If it does not replicate, the rate of virus-induced tumor cell killing should be maximized. If the virus does replicate, the rate of virus-induced cell killing should be kept small. If the virus is too lytic in cancer cells, viral spread is compromised, resulting in persistence of both virus and tumor. This has important implications for choosing the correct techniques to evaluate replicating viruses in culture. A low multiplicity of infection must be used for evaluation, because this mimicks the spread of the virus through an established tumor. If a high multiplicity of infection is used, the virus that appears most efficient in this evaluation can be least efficient at eradicating the cancer in vivo. Theoretical results are discussed in the context of experimental data.