Development of a murine model of tumor promotion and progression for immunotoxicity testing

Abstract

Non‐selective immunosuppressive drugs are associated with an increased risk of neoplasia. Although selective immunosuppressants, e.g., monoclonal antibodies, will likely pose less of a hazard, concerns remain about an increased risk of neoplasia, particularly squamous cell carcinoma. The 2 year bioassay has been the industry standard for evaluating carcinogenicity. However, it has poor predictive value for immunosuppressive drugs, accurately identifying a hazard with only 5 of the 13 drugs tested. Thus, there is need for an alternative testing strategy. We have developed a novel 3‐stage model to study tumor promotion and progression in vivo. We chose a murine squamous skin cell carcinoma (SCC VII) cell line to study local invasion and dissemination, colonization, and tumor progression in C3H‐HeN, SCID and SCID/bg mice in the presence and absence of cyclosporin A. Local invasion and dissemination were evaluated by following emigration of quantum dot labeled tumor cells to the draining lymph node. Lung colony counts were made after iv injection of tumor cells and angiogenesis and growth fraction were evaluated morphometrically. Immunosuppression, was associated with increased local growth and lung colonization but with decreased angiogenesis and growth rates. These results suggest that a series of models described here may offer a viable alternative to the 2 year bioassay.