Transformation and Growth of Lung Adenomas in Mice Exposed to Urethane
Murine lung adenomas are benign tumors that may progress to malignant carcinoma. To gain insight into the mechanisms of urethane-induced lung carcinogenesis, we compare results from two experiments, each involving the addition of urethane to the drinking water of mice. In the first (the chronic experiment), animals were dosed continuously throughout the study. In the second (the acute experiment), animals were dosed only for a single two week period. In both experiments, animals were sacrificed at two week intervals from start of exposure. At each sacrifice all visible lung adenomas were counted and measured for size. We use the data from these experiments to test two hypotheses about the effects of chronic urethane exposure on adenoma transformation and growth. The transformation independence hypothesis postulates that each two-week exposure to urethane induces adenomas independently of all other such exposures. This hypothesis would hold if each adenoma resulted from a single transforming event, and if urethane had no effect on the proliferation rate of normal stem cells. The growth independence hypothesis postulates that adenoma growth is independent of urethane exposure. This hypothesis would hold if urethane had no effect on the proliferation rate of transformed adenoma-progenitor cells. We use the maximum likelihood method to test these hypotheses, and find that both are rejected by the data. Using the Double Poisson distribution , we also examine inter-animal dispersion in adenoma counts, and the consequences of overdispersion for hypothesis testing. Although the severe overdispersion found in these data substantially reduced the significance of the likelihood ratio statistic for the transformation independence hypothesis, the hypothesis still was rejected. Overdispersion had little effect on the likelihood ratio statistic that rejected the growth independence hypotheses. Reasons for rejection of the two hypotheses are discussed.
Keywordsadenomas carcinogenesis cell transformation clonal growth Double Poisson distribution EM algorithm maximum likelihood urethane
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