INCREASED CELL PROLIFERATION WITH PERSISTENCE OF CIRCADIAN RHYTHMS IN HAMSTER CHEEK POUCH NEOPLASMS

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Abstract
Squamous cell neoplasms induced by repeated topical application of 7,12-dimethyl-benz(a)anthracene in Syrian hamster cheek pouch exhibited circadian rhythms of DNA synthesis and mitotic activity. Fluctuations in the fractions of cells in mitosis and DNA synthesis observed in the tumors were approximately in phase with the circadian rhythms from normal precursor epithelium, indicating that some degree of host physiologic modulation persists during neoplastic growth. The labeling (thymidine-3H) and mitotic indices of neoplasms were considerably higher than normal throughout the 24 h period. The duration of the neoplastic S phase, measured from the PLM [percent labeled mitosis] curve, was 30% shorter than normal; G2 did not show detectable variation. The data demonstrated that chemically induced squamous cell neoplasms had markedly increased rates of cell production. Applications of a carcinogen on a cell-renewing population generate a multicompartmental cytokinetic imbalance in which; a higher proportion of G0 cells is stimulated to enter the cycle; the duration of the cell cycle is shortened; the regulatory mechanisms fail to stimulate an accelerated rate of differentiation to compensate for the overproduction of cells and the state of proliferative hyperactivity becomes stable. An oncogenic cytokinetic mechanism based on a persistent decrease in cell loss (differentiation) is ruled out by the present investigation, at least for squamous cell neoplasms.