S. Taneja et al., Enhanced antitumor efficacy of a herpes simplex virus mutant isolated by genetic selection in cancer cells, P NAS US, 98(15), 2001, pp. 8804-8808
Citations number
25
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Replication-competent, attenuated herpes simplex virus-1 (HSV-1) derivative
s that contain engineered mutations into the viral gamma 34.5 virulence gen
e have been used as oncolytic agents. However, as attenuated mutants often
grow poorly, they may not completely destroy some tumors and surviving canc
er cells simply regrow. Thus, although HSV-1 gamma 34.5 mutants can reduce
the growth of human tumor xenografts in mice and have passed phase I safety
studies, their efficacy is limited because they replicate poorly in many h
uman tumor cells. Previously, we selected for a gamma 34.5 deletion mutant
variant that regained the ability to replicate efficiently in tumor cells.
Although this virus contains an extragenic suppressor mutation that confers
enhanced growth in tumor cells, it remains attenuated. Here, we demonstrat
e that the suppressor virus replicates to greater levels in prostate carcin
oma cells and, importantly, is a more potent inhibitor of tumor growth in a
n animal model of human prostate cancer than the gamma 34.5 parent virus. T
hus, genetic selection in cancer cells can be used as a tool to enhance the
antitumor activity of a replication-competent virus. The increased therape
utic potency of this oncolytic virus may be useful in the treatment of a wi
de variety of cancers.