The nitroreductase prodrug SN 28343 enhances the potency of systemically administered armed oncolytic adenovirus ONYX-411(NTR).
Conditionally replicating adenoviruses (CRAd) 'armed' with prodrug-activating genes have the potential to augment the efficacy of virotherapy. An Escherichia coli nitroreductase (NTR) gene (nfsB) was introduced into the E3B region of the systemically active CRAd ONYX-411, to produce ONYX-411(NTR), which had single agent oncolytic activity equivalent to unarmed virus in vitro and in vivo. A fluorogenic probe (SN 29884) developed to monitor NTR expression revealed robust, durable NTR expression in ONYX-411(NTR) infected neoplastic but not primary human cell lines. NTR expression occurred >24 h post-infection in parallel with fiber and was sensitive to ara-C indicating transcriptional linkage to viral replication. A novel NTR prodrug, the 3,5-dinitrobenzamide-2-bromomustard SN 27686, was shown to be more dose potent and selective than CB 1954 and provided a superior bystander effect in 3D multicellular layer cultures. Its water-soluble phosphate ester SN 28343 was substantially more active than CB 1954 against xenografts containing a minority of stable NTR-expressing cells. A single intravenous dose of ONYX-411(NTR) (10(8) PFU) to nude mice bearing large H1299 xenografts (>350 mm(3)) resulted in tumor-specific NTR expression which increased over time. Despite extensive viral spread by day 14, this conservative virus dose and schedule was unable to control such well-established tumors. However, subsequent administration of SN 28343 resulted in the majority of mice (62.5%) being tumor-free on day 120.
Singleton
D C
DC
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
Li
D
D
Bai
S Y
SY
Syddall
S P
SP
Smaill
J B
JB
Shen
Y
Y
Denny
W A
WA
Wilson
W R
WR
Patterson
A V
AV
D000256:Adenoviridae; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001388:Aziridines / Q000494:pharmacology; D029968:Escherichia coli Proteins / Q000096:biosynthesis* / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D009601:Nitroreductases / Q000096:biosynthesis* / Q000235:genetics; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000201:enzymology / Q000235:genetics; D011355:Prodrugs / Q000494:pharmacology*; D013997:Time Factors; D014161:Transduction, Genetic; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001388:Aziridines; D029968:Escherichia coli Proteins; D009588:Nitrogen Mustard Compounds; D011355:Prodrugs; C526874:SN 28343; C100099:tretazicar; C116054:NfsB protein, E coli; D009601:Nitroreductases