Antitumoral effect of interleukin-12-secreting fibroblasts in a mouse model of ovarian cancer: implications for the use of ovarian cancer biopsy-derived fibroblasts as a vehicle for regional gene therapy.
Fibroblasts can easily be cultured from human solid ovarian tumor biopsies and are readily transfected using retroviral vectors. To test the feasibility of using these cells as a vehicle for regional, intraperitoneal (i.p.) ovarian cancer gene therapy, we first examined the behavior of murine fibroblasts transduced with the neoR marker gene and injected i.p. in syngeneic mice. We found that these fibroblasts were not invasive and formed clusters preferentially attached to the pancreatic and hepatic mesentery, where they survived for at least 30 days and continued to express neoR. We subsequently assessed the effect of regional delivery of murine interleukin-12 (mIL-12)-secreting fibroblasts in a syngeneic immunocompetent mouse model of ovarian cancer (ID8). ID8 ovarian tumor cells were injected i.p. into one flank. Our results show a survival of 88% at 120 days postinjection of animals treated with mIL-12-secreting fibroblasts i.p. in the other flank on the same day as injection of tumor cells. At that time, all animals coinoculated with ID8 cells and unmodified fibroblasts had been or needed to be culled because of advanced neoplastic disease (P < 10(-5), log-rank test). Furthermore, animals treated with mIL-12-secreting fibroblasts had a statistically significant decrease in tumor burden, as measured by diaphragm weight, relative to mock-treated groups (P = .0032, H-test). Our histological data show evidence for both immunological and anti-angiogenic mechanisms being implicated in this antitumoral effect. In addition, no signs of IL-12-induced toxicity were observed in any of the tissue sections analyzed. Taken together, our findings suggest that ovarian tumor biopsy-derived fibroblasts are a safe and efficacious vehicle for i.p. delivery of IL-12 as a regional secondary treatment for minimal residual disease of ovarian cancer.
Sanches
R
R
Laboratoire de Thérapie Génique Humaine et Expérimentale, INSERM CRI 9502/EA 2145, Clermont-Ferrand, France.
Kuiper
M
M
Penault-Llorca
F
F
Aunoble
B
B
D'Incan
C
C
Bignon
Y J
YJ
D000818:Animals; D001706:Biopsy; D015139:Blotting, Southern; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D018664:Interleukin-12 / Q000235:genetics* / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000473:pathology / Q000628:therapy*; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy*; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014018:Tissue Distribution; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D018664:Interleukin-12