The enhanced tumor selectivity of an oncolytic vaccinia lacking the host range and antiapoptosis genes SPI-1 and SPI-2.
The ability of cancer cells to evade apoptosis may permit survival of a recombinant vaccinia lacking antiapoptotic genes in cancer cells compared with normal cells. We have explored the deletion of two vaccinia virus host range/antiapoptosis genes, SPI-1 and SPI-2, for their effects on the viral replication and their ability to induce cell death in infected normal and transformed cells in vitro. Indeed, in three paired normal and transformed cell types, the SPI-1 and SPI-2 gene-deleted virus (vSP) preferentially replicates in transformed cells or p53-null cells when compared with their normal counterparts. This selectivity may be derived from the fact that vSP-infected normal cells died faster than infected cancer cells. A fraction of infected cells died with evidence of necrosis as shown by both flow cytometry and detection of high-mobility group B1 protein released from necrotic cells into the culture supernatant. When administered to animals, vSP retains full ability to replicate in tumor tissues, whereas replication in normal tissues is greatly diminished. In a model of viral pathogenesis, mice treated with vSP survived substantially longer when compared with mice treated with the wild-type virus. The mutant virus vSP displayed significant antitumoral effects in an MC38 s.c. tumor model in both nude (P < 0.001) and immunocompetent mice (P < 0.05). We conclude that this recombinant vaccinia vSP shows promise for oncolytic virus therapy. Given its enhanced tumor selectivity, improved safety profile, and substantial oncolytic effects following systemic delivery in murine models, it should also serve as a useful vector for tumor-directed gene therapy.
Guo
Z Sheng
ZS
Division of Surgical Oncology, University of Pittsburgh Cancer Institute, PA 15232, USA.
Naik
Arpana
A
O'Malley
Mark E
ME
Popovic
Petar
P
Demarco
Richard
R
Hu
Yun
Y
Yin
Xiaoyu
X
Yang
Shuting
S
Zeh
Herbert J
HJ
Moss
Bernard
B
Lotze
Michael T
MT
Bartlett
David L
DL
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D005260:Female; D017353:Gene Deletion; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D014616:Vaccinia virus / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D014779:Virus Replication