title: Development of a squamous cell carcinoma mouse model for immunotoxicity testing.
abstract: An important component of safety assessment of new pharmaceuticals is evaluation of their potential to increase the risk of developing cancer in humans. The traditional 2-year rodent bioassay often is not feasible or scientifically applicable for evaluation of biotherapeutics. Additionally, it has poor predictive value for non-genotoxic immunosuppressive compounds. Thus, there is a need for alternative testing strategies. A novel 3-stage tumor model in syngeneic C3H/HeN mice was evaluated here to study the effects of immunosuppressive drugs on tumor promotion and progression in vivo. The model employed a skin squamous cell carcinoma cell line (SCC VII) due to the increased prevalence of squamous cell carcinoma (SCC) in humans associated with immunosuppression after transplants. Local invasion, colonization and tumor progression were evaluated. The validation set of immunosuppressive drugs included: Cyclosporin (CSA), cyclophosphamide (CTX), azathioprine, etanercept, abatacept and prednisone. Local invasion was evaluated by histological assessment as well as fluorescence trafficking from Qdot(®)-labeled tumor cells from the site of inoculation to the draining lymph node. Colonization was evaluated by lung colony counts following intravenous inoculation. Tumor progression was assessed by morphometric analysis of lesion area, angiogenesis and growth fraction of established metastatic neoplasia. Immunosuppressive drugs in the validation set yielded mixed results, including decreased progression. The methods and results described herein using an in vivo syngeneic mouse tumor model can provide insight about the assessment of immunosuppressive drugs in carcinogenicity risk assessment.
authors.affiliation: a Biologics Toxicology and.
authors.forename: Devon D
authors.initials: DD
authors.lastname: Sominski
authors.affiliation: a Biologics Toxicology and.
authors.forename: Patricia
authors.initials: P
authors.lastname: Rafferty
authors.affiliation: a Biologics Toxicology and.
authors.forename: Kerry
authors.initials: K
authors.lastname: Brosnan
authors.affiliation: a Biologics Toxicology and.
authors.forename: Amy
authors.initials: A
authors.lastname: Volk
authors.affiliation: a Biologics Toxicology and.
authors.forename: Mindi
authors.initials: M
authors.lastname: Walker
authors.affiliation: a Biologics Toxicology and.
authors.forename: Dorie
authors.initials: D
authors.lastname: Capaldi
authors.affiliation: a Biologics Toxicology and.
authors.forename: Eva
authors.initials: E
authors.lastname: Emmell
authors.affiliation: b Non-clinical Statistics, Janssen Research & Development, LLC , Spring House , PA , USA.
authors.forename: Kjell
authors.initials: K
authors.lastname: Johnson
authors.affiliation: a Biologics Toxicology and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Weinstock
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D012878:Skin Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents
keywords: C3H/HeN; SCC VII; carcinogenicity; immunosuppression; immunosuppressive drugs; immunotoxicology; metastasis; mouse; squamous cell carcinoma