In vitro analysis of cidofovir and genetically engineered TK expression as potential approaches for the intervention of ColoAd1-based treatment of cancer.
We have generated a novel oncolytic Adenovirus (Ad), ColoAd1, with significantly increased potency ( approximately 100-fold) relative to its parent viruses, Ad11p and Ad3, or to the clinically tested oncolytic Ad, ONYX-015. Although this agent has a significant increase in its therapeutic window relative to ONYX-015 or its parent viruses, its ability to intervene and control virotherapy in treated patient is an important safety consideration for a novel biological therapy, such as ColoAd1. As there are no approved treatments for Ad infections, we sought to define whether antivirals being used to experimentally treat Ad infections (cidofovir (CDV), ribavirin) had any activity against ColoAd1. In addition, we incorporated a well-described pro-drug converting enzyme, the herpes simplex virus-thymidine kinase (HSV-TK) gene, into the viral genome to test whether the expression of this enzyme directly from the virus could be exploited as a safety valve for arresting the viral infection in the presence of the pro-drug, ganciclovir. Both the antiviral drug, CDV, and the incorporation of the pro-drug-converting TK enzyme were validated as effective approaches to controlling ColoAd1 infection, and this represents an important advancement in the development of ColoAd1 as an anticancer treatment.
Bauzon
M
M
Bayer Healthcare Pharmaceuticals, Protein Therapeutics, Richmond, CA 94806, USA.
Jin
F
F
Kretschmer
P
P
Hermiston
T
T
D000256:Adenoviridae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000472:pathogenicity*; D000257:Adenoviridae Infections / Q000517:prevention & control*; D000998:Antiviral Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005818:Genetic Engineering / Q000379:methods; D006801:Humans; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods; D050504:Oncolytic Viruses / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity*; D063065:Organophosphonates / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology; D012254:Ribavirin / Q000494:pharmacology; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D063065:Organophosphonates; D011355:Prodrugs; D012254:Ribavirin; D003596:Cytosine; D013937:Thymidine Kinase; D000077404:Cidofovir