In vivo antitumor activity of ONYX-015 is influenced by p53 status and is augmented by radiotherapy.
The E1B-deleted, replication-competent ONYX-015 (dl1520) adenovirus was originally described as being able to selectively kill p53-deficient cells due to a requirement of p53 inactivation for efficient viral replication. This hypothesis has become controversial because subsequent in vitro studies have demonstrated that the host range specificity of ONYX-015 is independent of p53 gene status. Using a pair of isogenic cell lines that differ only in their p53 status, we demonstrate here that although ONYX-015 can replicate in both p53 wild-type and mutant cells in vitro, the virus demonstrates significantly greater antitumor activity against mutant p53 tumors in vivo. Moreover, ONYX-015 viral therapy can be combined with radiation to improve tumor control beyond that of either monotherapy. The results demonstrate that ONYX-015 can discern in vivo between tumors having a different p53 status and that it may be an effective neoadjuvant to radiation therapy.
Rogulski
K R
KR
Department of Radiation Oncology, Henry Ford Health System, Detroit, Michigan 48202, USA.
Freytag
S O
SO
Zhang
K
K
Gilbert
J D
JD
Paielli
D L
DL
Kim
J H
JH
Heise
C C
CC
Kirn
D H
DH
D000256:Adenoviridae; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D020360:Neoadjuvant Therapy; D009369:Neoplasms / Q000235:genetics* / Q000532:radiotherapy / Q000628:therapy*; D014407:Tumor Cells, Cultured