Effective antitumoral immune responses are not induced by cytosine deaminase suicide gene transfer in a syngeneic rat pancreatic carcinoma model.
BACKGROUND
Experimental gene transfer can make tumors more immunogenic, leading to local regression and inducing immunological memory sufficient to permit resistance to a tumor rechallenge. However, this rarely had any significant impact on large established tumors.


METHODS
To analyze potential immunological effects, we used weakly immunogenic pancreatic carcinomas in syngeneic, immunocompetent Lewis rats and performed in situ adenoviral mediated cytosine deaminase (CD) gene transfer followed by administration of the prodrug, 5-fluorocytosine (5FC). In order to reflect the clinical situation, such treated tumors were surgically resected and animals were rechallenged with parental DSL6A pancreatic tumor cells. Tumor growth and cytotoxic activity of immune cells were determined.


RESULTS
CD/5FC treatment of the DSL6A cells revealed significant induction of apoptosis in vitro and slowed down tumor progression in syngeneic hosts. Furthermore, we observed neither significant change in tumor growth nor protective immunity in the rechallenged animals. Analysis of T lymphocytes showed no specific cytotoxic activity against DSL6A cells. There was only a trend towards a minor NK cell activation.


CONCLUSIONS
Albeit the present study failed to induce protective antitumor immunity, the initial finding of reduced tumor growth argues for the development of multimodal therapeutic options to overcome negative impacts of advanced malignant disease or chemotherapy-related anergy and immunosuppression.
Eisold
Sven
S
Department of General Surgery, Thoracic and Vascular Surgery, University of Rostock, Rostock, Germany.
Antolovic
Dalibor
D
Schmidt
Jan
J
Wiessner
Reiko
R
Klar
Ernst
E
von Knebel-Doeberitz
Magnus
M
Linnebacher
Michael
M
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D043525:Cytosine Deaminase / Q000235:genetics*; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D005437:Flucytosine / Q000627:therapeutic use*; D022761:Gene Transfer, Horizontal; D015316:Genetic Therapy; D008297:Male; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051381:Rats; D011917:Rats, Inbred Lew
D005437:Flucytosine; D043525:Cytosine Deaminase