title: 5-Fluorocytosine-induced eradication of murine adenocarcinomas engineered to express the cytosine deaminase suicide gene requires host immune competence and leaves an efficient memory.
abstract: The nonmammalian cytosine deaminase (CD) enzyme converts the nontoxic prodrug 5-fluorocytosine (5-FC) to the toxic metabolite 5-fluorouracil. Parental cells of a mammary adenocarcinoma (TSA-pc) of BALB/c mice were transfected with the CD gene (TSA-CD), and the ability of 5-FC to hamper their growth was evaluated. A quantity amounting to 0.5 mg of 5-FC/0.3 ml of medium inhibits the proliferation of TSA-CD cells, but not that of TSA-pc, nor that of TSA-pc transfected with neomycin-resistance gene only (TSA-neo). In BALB/c mice, 800 mg 5-FC/kg of body weight injected daily i.p. for 30 days causes total regression of incipient (1-day-old), and established (3- and 7-day-old) TSA-CD tumors, and of 3-day-old experimental lung metastases, but does not impair TSA-pc nor TSA-neo cell growth. Because in CD8+ T lymphocyte- and granulocyte-depleted mice 5-FC no longer impairs TSA-CD growth, immune mechanisms appear to play an important role in this regression. Following, regression, all mice are resistant to subsequent s.c. or i.v. lethal challenges with TSA-pc. The induction of this immune memory is dependent on CD4+ lymphocytes, whereas its effector phase depends on both CD4+ and CD8+ lymphocytes. The memory elicited in tumor-bearing mice by the 5-FC-dependent regression of TSA-CD tumors cures a significant number of mice with 4-day-old TSA-pc metastases, but does not impair the growth of 4-day-old solid s.c. tumors. The reliability of this regression and the subsequent establishment of an efficient immune memory against poorly immunogenic TSA-pc offer the prospect that CD-transduced tumor cells and 5-FC can be used as components of a live antitumor vaccine.
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Consalvo
authors.forename: C A
authors.initials: CA
authors.lastname: Mullen
authors.forename: A
authors.initials: A
authors.lastname: Modesti
authors.forename: P
authors.initials: P
authors.lastname: Musiani
authors.forename: A
authors.initials: A
authors.lastname: Allione
authors.forename: F
authors.initials: F
authors.lastname: Cavallo
authors.forename: M
authors.initials: M
authors.lastname: Giovarelli
authors.forename: G
authors.initials: G
authors.lastname: Forni
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000556:secondary / Q000628:therapy*; D000818:Animals; D003131:Combined Modality Therapy; D043525:Cytosine Deaminase; D005260:Female; D005437:Flucytosine / Q000627:therapeutic use*; D015316:Genetic Therapy; D007156:Immunologic Memory / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009700:Nucleoside Deaminases / Q000096:biosynthesis / Q000235:genetics*; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase