Double suicide gene therapy augments the antitumor activity of a replication-competent lytic adenovirus through enhanced cytotoxicity and radiosensitization

Hum Gene Ther. 2000 Jan 1;11(1):67-76. doi: 10.1089/10430340050016166.

Abstract

Replication-competent adenoviruses may provide a highly efficient means of delivering therapeutic genes to tumors. Previously, we evaluated in vitro a replication-competent adenovirus (Ad5-CD/TKrep) containing a cytosine deaminase (CD)/herpes simplex type 1 thymidine kinase (HSV-1 TK) fusion gene that allows lytic viral therapy to be combined with double suicide gene therapy. Both the CD/5-FC and HSV-1 TK/GCV enzyme/prodrug systems enhanced the tumor cell-specific cytopathic effects of the Ad5-CD/TKrep virus in vitro and sensitized cells to radiation. To extend these in vitro findings in vivo, we evaluated the antitumor activity of the Ad5-CD/TKrep virus in combination with double prodrug therapy and radiation therapy. The Ad5-CD/TKrep virus independently demonstrated significant antitumor activity against C33A cervical carcinoma xenografts. Therapeutic outcome was dramatically improved with systemic administration of double, but not single, prodrug (5-FC + GCV) therapy. When used in a neoadjuvant setting, Ad5-CD/TKrep-mediated double suicide gene therapy dramatically potentiated the effectiveness of radiation therapy. The trimodal approach of Ad5-CD/TKrep viral, double suicide gene, and radiotherapies produced significant tumor regression and ultimately 100% tumor cure. The results demonstrate the high therapeutic potential of the trimodal approach and provide a solid foundation for future clinical trials.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / enzymology
  • Adenoviridae / genetics*
  • Adenoviridae / physiology
  • Animals
  • Artificial Gene Fusion
  • Cell Survival
  • Combined Modality Therapy
  • Cytosine Deaminase
  • Female
  • Genetic Therapy*
  • Genetic Vectors
  • Herpesvirus 1, Human / enzymology
  • Injections, Intralesional
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Neoplasms, Experimental / radiotherapy
  • Neoplasms, Experimental / therapy*
  • Nucleoside Deaminases / genetics
  • Radiation Tolerance
  • Thymidine Kinase / genetics
  • Virus Replication

Substances

  • Thymidine Kinase
  • Nucleoside Deaminases
  • Cytosine Deaminase