Efficient prodrug activator gene therapy by retroviral replicating vectors prolongs survival in an immune‐competent intracerebral glioma model

Shih Han Chen, Jui Ming Sun, Bing Mao Chen, Sheng Che Lin, Hao Fang Chang, Sara Collins, Deching Chang, Shu Fen Wu, Yin Che Lu, Weijun Wang, Thomas C. Chen, Noriyuki Kasahara, Hsin Ell Wang, Chien Kuo Tai

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Prodrug activator gene therapy mediated by murine leukemia virus (MLV)‐based retroviral replicating vectors (RRV) was previously shown to be highly effective in killing glioma cells both in culture and in vivo. To avoid receptor interference and enable dual vector co‐infection with MLV‐RRV, we have developed another RRV based on gibbon ape leukemia virus (GALV) that also shows robust replicative spread in a wide variety of tumor cells. We evaluated the potential of GALV‐based RRV as a cancer therapeutic agent by incorporating yeast cytosine deaminase (CD) and E. coli nitroreductase (NTR) prodrug activator genes into the vector. The expression of CD and NTR genes from GALV‐RRV achieved highly efficient delivery of these prodrug activator genes to RG‐2 glioma cells, resulting in enhanced cytotoxicity after administering their respective prodrugs 5‐fluorocytosine and CB1954 in vitro. In an immune‐competent intracerebral RG‐2 glioma model, GALV‐mediated CD and NTR gene therapy both significantly suppressed tumor growth with CB1954 administration after a single injection of vector supernatant. However, NTR showed greater potency than CD, with control animals receiving GALV‐NTR vector alone (i.e., without CB1954 prodrug) showing extensive tumor growth with a median survival time of 17.5 days, while animals receiving GALV‐NTR and CB1954 showed significantly prolonged survival with a median survival time of 30 days. In conclusion, GALV‐RRV enabled high‐efficiency gene transfer and persistent expression of NTR, resulting in efficient cell killing, suppression of tumor growth, and prolonged survival upon CB1954 administration. This validates the use of therapeutic strategies employing this prodrug activator gene to arm GALV‐RRV, and opens the door to the possibility of future combination gene therapy with CD‐armed MLV‐RRV, as the latter vector is currently being evaluated in clinical trials.

Original languageEnglish (US)
Article number1433
JournalInternational journal of molecular sciences
Volume21
Issue number4
DOIs
StatePublished - Feb 2020

Keywords

  • Brain tumor
  • E.coli nitroreductase gene
  • Gene therapy
  • Prodrug activator
  • Retroviral replicating vector

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Fingerprint Dive into the research topics of 'Efficient prodrug activator gene therapy by retroviral replicating vectors prolongs survival in an immune‐competent intracerebral glioma model'. Together they form a unique fingerprint.

  • Cite this

    Chen, S. H., Sun, J. M., Chen, B. M., Lin, S. C., Chang, H. F., Collins, S., Chang, D., Wu, S. F., Lu, Y. C., Wang, W., Chen, T. C., Kasahara, N., Wang, H. E., & Tai, C. K. (2020). Efficient prodrug activator gene therapy by retroviral replicating vectors prolongs survival in an immune‐competent intracerebral glioma model. International journal of molecular sciences, 21(4), [1433]. https://doi.org/10.3390/ijms21041433