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The Predictive Value of Skin Allograft Survival Times during the Development of Urethan-induced Lung Adenomas in BALB/c Mice¹

Cancer Research Genetics Laboratory and Department of Bacteriology and Immunology, University of California, Berkeley, California 94720 [M. A. L.], and The Institute for Cancer Research, Philadelphia, Pennsylvania 19111 [R. T. P.]

The possibility that depression of cell-mediated immunity facilitates the carcinogenic effect of urethan on the mouse lung was studied in the BALB/c strain which is highly susceptible to lung tumor development. Lung adenomas were induced by giving 4-day-old mice an i.p. injection of 1.0 mg urethan. Two months after injection, urethan-treated and 0.85% NaCl solution-treated control mice were test grafted with DBA/2 skin (H-2^d H-2^d). In the 1st experiment, urethan caused a modest impairment of graft rejection as indicated by a skewing and flattening of the normal distributions of survival scores in treated mice: 64% of 36 urethan-treated mice had rejection times slower than the control median. Two months after grafting, lung adenomas were found preferentially in these mice rather than in mice with shorter rejection times.

In the 2nd experiment, thymectomy and sham thymectomy were performed 2 to 3 days before urethan treatment. Thymectomized mice of both sexes developed significantly more lung adenomas than did sham-thymectomized controls. Thymectomized males, but not females, had significantly larger adenomas than did controls. Among males, large adenomas occurred in slow allograft rejectors more frequently than expected by chance. Deaths from large, obstructive lung adenomas occurred exclusively among the slowest rejectors whether or not they had intact thymuses. Based on the combined data of the 2 experiments, allograft survival scores were significantly correlated with lung adenoma incidence. We concluded that skin allograft survival scores after urethan treatment provide a useful index of the risk of lung tumor development in BALB/c mice. This relationship can be explained by assuming that cell-mediated immunity normally modifies the expression of the carcinogenic effect of urethan on the mouse lung.

Our findings are interpreted as further evidence for the operation of immunological surveillance during chemical carcinogenesis.

¹ This investigation was supported by USPHS CA-05388 from the National Cancer Institute.

² Aided by a fellowship from the Anna Fuller Fund.

³ Supported by USPHS Grants CA-08856, CA-06927, and FR-05539 from the National Cancer Institute, Grant IN-49 from the American Cancer Society, and an appropriation from the Commonwealth of Pennsylvania.

Received 10/ 6/69. Accepted 12/18/69.