Combined treatment, based on lysomustine administration with mesenchymal stem cells expressing cytosine deaminase therapy, leads to pronounced murine Lewis lung carcinoma growth inhibition

J Gene Med. 2016 Sep;18(9):220-33. doi: 10.1002/jgm.2894.

Abstract

Background: The combination of stem cell-based gene therapy with chemotherapy comprises an advantageous strategy that results in a reduction of system toxicity effects and an improvement in the general efficacy of treatment. In the present study, we estimated the efficacy of adipose tissue-derived mesenchymal stem cells (AT-MSCs) expressing cytosine deaminase (CDA) combined with lysomustine chemotherapy in mice bearing late stage Lewis lung carcinoma (LLC).

Methods: Adipose tissue-derived mesenchymal stem cells were transfected with non-insert plasmid construct transiently expressing fused cytosine deaminase-uracil phosphoribosyltransferase protein (CDA/UPRT) or the same construct fused with Herpes Simplex Virus Type1 tegument protein VP22 (CDA/UPRT/VP22). Systemic administration of 5-fluorocytosine (5FC) and lysomustine was implemented after a single intratumoral injection of transfected AT-MSCs.

Results: We demonstrated that direct intratumoral transplantation of AT-MSCs expressing CDA/UPRT or CDA/UPRT/VP22 followed by systemic administration of 5FC resulted in a significant tumor growth inhibition. There was a 56% reduction in tumor volume in mice treated by AT-MSCs-CDA/UPRT + 5FC or with AT-MSCs-CDA/UPRT/VP22 + 5FC compared to control animals grafted with lung carcinoma alone. Transplantation of AT-MSCs-CDA/UPRT + 5FC and AT-MSCs-CDA/UPRT/VP22 + 5FC prolonged the life span of mice bearing LLC by 27% and 31%, respectively. Co-administration of lysomustine and AT-MSCs-CDA/UPRT + 5FC led to tumor growth inhibition (by 86%) and life span extension (by 60%) compared to the control group.

Conclusions: Our data indicate that a combination CDA/UPRT-expressing AT-MSCs with lysomustine has a superior antitumor effect in the murine lung carcinoma model compared to monotherapies with transfected AT-MSCs or lysomustine alone, possibly because of a synergistic effect of the combination therapy. Copyright © 2016 John Wiley & Sons, Ltd.

Keywords: Lewis lung carcinoma; cytosine deaminase; lysomustine; mesenchymal stem cells; suicide gene therapy.

MeSH terms

  • Adipose Tissue / cytology
  • Animals
  • Carcinoma, Lewis Lung / genetics
  • Carcinoma, Lewis Lung / pathology
  • Carcinoma, Lewis Lung / therapy*
  • Cell Line, Tumor
  • Combined Modality Therapy
  • Cytosine Deaminase / genetics
  • Cytosine Deaminase / metabolism*
  • Female
  • Flucytosine / administration & dosage
  • Flucytosine / pharmacology
  • Genetic Therapy / methods
  • Male
  • Mesenchymal Stem Cell Transplantation / methods*
  • Mesenchymal Stem Cells / metabolism*
  • Mice, Inbred C57BL
  • Nitrosourea Compounds / administration & dosage
  • Nitrosourea Compounds / pharmacology*
  • Pentosyltransferases / genetics
  • Pentosyltransferases / metabolism
  • Survival Analysis
  • Tumor Burden / drug effects
  • Tumor Burden / genetics

Substances

  • Nitrosourea Compounds
  • lysomustine
  • Flucytosine
  • Pentosyltransferases
  • uracil phosphoribosyltransferase
  • Cytosine Deaminase