A prodrug strategy using ONYX-015-based replicating adenoviruses to deliver rabbit carboxylesterase to tumor cells for conversion of CPT-11 to SN-38.
ONYX-015 has been used successfully in the clinic as a cancer therapeutic in combination with chemotherapy. The combination of ONYX-015 and chemotherapy appears to be more efficacious than either regimen alone. In this study, we try to enhance this combination by "arming" ONYX-015 with a therapeutic transgene, an approach more commonly used with nonreplicating viruses in the context of gene therapy. We chose the prodrug converting enzyme carboxylesterase (CE), which converts the camptothecin derivative CPT-11 (irinotecan) to the much more potent chemotherapeutic SN-38. The transgene was introduced into three distinct positions in the E3 region of the adenovirus genome to allow either early or late expression during the virus life cycle. We demonstrate that each of these ONYX-015-based adenoviruses expresses an active CE enzyme that can efficiently convert CPT-11 to SN-38. Furthermore, the cytotoxicity of CE-expressing viruses, but not control viruses, is enhanced significantly in the presence of the prodrug. Finally, we demonstrate that we can achieve transgene expression and activity in vivo in a human tumor xenograft model, and that treatment with a CE-expressing virus in combination with CPT-11 enhances survival of tumor-bearing mice. These results indicate that the addition of a prodrug converting enzyme may be a feasible approach to additionally enhance the efficacy of replicating adenoviruses as cancer therapeutics.
Onyx Pharmaceuticals, Richmond, California 94806, USA. hstubdal@post.harvard.edu
Hilde
H
Stubdal
Noah
N
Perin
Marilyn
M
Lemmon
Patricia
P
Holman
Maxine
M
Bauzon
Philip M
PM
Potter
Mary K
MK
Danks
Ali
A
Fattaey
Thomas
T
Dubensky
Leisa
L
Johnson
D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology; D043182:Carboxylesterase / Q000235:genetics* / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000628:therapy; D005260:Female; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000494:pharmacology; D011817:Rabbits; D019076:Transgenes; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D011355:Prodrugs; D000077146:Irinotecan; D043182:Carboxylesterase; D002166:Camptothecin