The role of the E1B 55 kDa gene product in oncolytic adenoviral vectors expressing herpes simplex virus-tk: assessment of antitumor efficacy and toxicity.
In this study, we evaluated three herpes simplex virus-1 thymidine kinase (HSV-tk) carrying replication-competent adenoviral vectors with and without the Ad5 E1B 55 kDa gene to assess whether this gene product has an influence on their antitumor efficacy, replication kinetics, and potential hepatotoxicity. Furthermore, we assessed the efficacy of these vectors in combination with ganciclovir (GCV). When compared with wild-type adenovirus, the recombinant vectors, in particular the E1B 55 kDa-deleted vector Ad.TK(RC)(II), generated a more efficiently cytopathic effect in proliferating cells, independently of their p53 phenotype. In a s.c. A549 lung cancer xenograft model, the cytoreductive effect of Ad.TK(RC)(II) was enhanced when followed by GCV treatment. In contrast, the efficacy of both E1B 55 kDa-positive vectors could not be further improved by GCV. In an i.p. MDAH 2774 ovarian cancer xenograft tumor model, the survival of animals treated with a prototypical replication-deficient adenovirus expressing HSV-tk (Ad.TK) was improved compared to controls when followed by GCV. In contrast, the cytoreductive efficacy of the replication-competent vectors was diminished when combined with the virostatic GCV. However, the antitumor effect of all replication-competent vectors was superior to combination chemotherapy with paclitaxel and carboplatin. In both tumor models, the oncolytic effect of the E1B 55 kDa-positive vectors was greater than that of Ad.TK(RC)(II). In an attempt to assess the toxicity of these vectors in a nonpermissive host, the viruses were administered systemically to immunocompetent and immunodeficient mice. Greater hepatotoxicity was seen with i.v. administration of the replication-competent viruses than with Ad.TK and in immunocompetent hosts, suggesting involvement of the immune system in the induction of tissue damage. The E1B 55 kDa gene had no significant influence on the liver toxicity of the vectors in this system. At therapeutic doses, intratumoral or i.p. injection of all vectors was well tolerated. Importantly, these replication-competent HSV-tk-expressing vectors were highly susceptible to GCV, representing an effective fail-safe mechanism to abolish viral replication in a clinical setting. Controllable intratumoral viral replication holds promise as a new treatment modality for cancer.
Wildner
O
O
Clinical Gene Therapy Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA. wildner@rrk-berlin.de
Morris
J C
JC
D017501:Adenovirus E1B Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000260:Adenoviruses, Human / Q000201:enzymology / Q000235:genetics* / Q000502:physiology; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D015774:Ganciclovir / Q000493:pharmacokinetics / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology* / Q000633:toxicity; D006367:HeLa Cells / Q000821:virology; D006561:Herpes Simplex / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D008107:Liver Diseases / Q000473:pathology / Q000821:virology; D008175:Lung Neoplasms / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000628:therapy; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology
D017501:Adenovirus E1B Proteins; D000998:Antiviral Agents; D011355:Prodrugs; D013937:Thymidine Kinase; D015774:Ganciclovir