title: Gene-directed enzyme prodrug therapy with carboxylesterase enhances the anticancer efficacy of the conditionally replicating adenovirus AdDelta24.
abstract: Conditionally replicating adenoviruses (CRAds) selectively replicate in and thereby kill cancer cells. The CRAd AdDelta24 with pRb-binding-deficient E1A kills cancer cells efficiently. Arming CRAds with genes encoding prodrug-converting enzymes could allow for enhanced anticancer efficacy by the combined effects of oncolytic replication and local prodrug activation. Here, we investigated combination treatment of human colon cancer cell lines with AdDelta24-type CRAds and gene-directed enzyme prodrug therapy (GDEPT) using two different enzyme/prodrug systems, that is, thymidine kinase/ganciclovir (TK/GCV) and carboxylesterase (CE)/CPT-11. On all three cell lines tested, GDEPT with TK/GCV made CRAd treatment less efficacious. In contrast, expression of a secreted form of CE (sCE2) combined with CPT-11 treatment markedly enhanced the efficacy of AdDelta24 virotherapy. Based on this observation, we constructed an AdDelta24 variant expressing sCE2. In the absence of CPT-11, this new CRAd Ad5-Delta24.E3-sCE2 was similarly effective as its parent in killing human colon cancer cells. Low concentrations of CPT-11 inhibited Ad5-Delta24.E3-sCE2 propagation. Nevertheless, CPT-11 specifically augmented the cytotoxicity of Ad5-Delta24.E3-sCE2 against all three-colon cancer cell lines. Hence, the positive contribution of sCE2/CPT-11 GDEPT to colon cancer cytotoxicity outweighed its negative influence on CRAd propagation. Therefore, CRAd-sCE2/CPT-11 combination therapy appears useful for more effective treatment of colon cancer.
authors.affiliation: Division of Gene Therapy, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Oosterhoff
authors.forename: H M
authors.initials: HM
authors.lastname: Pinedo
authors.forename: M A
authors.initials: MA
authors.lastname: Witlox
authors.forename: J E
authors.initials: JE
authors.lastname: Carette
authors.forename: W R
authors.initials: WR
authors.lastname: Gerritsen
authors.forename: V W
authors.initials: VW
authors.lastname: van Beusechem
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D000998:Antiviral Agents / Q000627:therapeutic use; D043182:Carboxylesterase / Q000235:genetics* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000628:therapy* / Q000821:virology; D003131:Combined Modality Therapy; D003588:Cytopathogenic Effect, Viral; D015774:Ganciclovir / Q000627:therapeutic use; D015870:Gene Expression; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D006801:Humans; D011355:Prodrugs / Q000008:administration & dosage* / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000627:therapeutic use; D013937:Thymidine Kinase / Q000627:therapeutic use; D014161:Transduction, Genetic / Q000379:methods; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D011355:Prodrugs; D011993:Recombinant Fusion Proteins; D013937:Thymidine Kinase; D043182:Carboxylesterase; D015774:Ganciclovir