Estimating the probability of initiated cell death before tumor induction

Abstract

The effects of cell toxicity are known to be inherent in carcinogenesis induced by radiation or chemical carcinogens. The event of cell death precludes tumor induction from occurring. A long standing problem is to estimate the proportion of initiated cells that die before tumor induction. No experimental techniques are currently available for directly gauging the rate of cell death over extended periods of time. The obstacle can be surmounted by newly developed theoretical methods of carcinogenesis modeling. In this paper, we apply such methods to published data on multiple lung tumors in mice receiving different schedules of urethane. Bioassays of this type play an important role in testing environmental chemicals for carcinogenic activity. Our estimates for urethane-induced carcinogenesis show that, unexpectedly, many initiated cells die early in the course of tumor promotion. We present numerical estimates for the probability of initiated cell death for different schedules (and doses) of urethane administration. Section 1As with many processes of carcinogenesis, the process of cell killing induced by a carcinogen is difficult to observe directly, and inferences rely on mathematical models. In a recent study (1), Moolgavkar et al. reported a statistical analysis of experimental data on enzyme-altered (ATPase-deficient) liver foci in rats induced by diethylnitrosamine. It is generally believed that these foci represent clones of initiated cells, and at least some of them eventually transform into malignant tumors. The authors used a two-stage birth-death-mutation model of carcinogenesis, usually referred to as the MoolgavkarVenzon-Knudson model (2, 3), to estimate the extinction probability for clones of altered cells in initiation-promotion experiments. In the absence of a promoter, the estimated extinction probability was higher than 0.99, and its value tended to decrease when two different promoters were applied; this effect can be attributed to stimulation of cell proliferation.The Moolgavkar-Venzon-Knudson model introduces the clonal expansion of initiated cells as the basic mechanism of tumor promotion. It is assumed that clonal growth begins immediately after initiation and can mathematically be described as a birth-and-death stochastic process. Under this model, the probability of a clone to become extinct is a natural summary characteristic of the susceptibility of initiated cells to death in the course of tumor development. However, there is experimental evidence that single initiated cells persist over an extended time period after the administration of a carcinogen. Using another biochemical marker (the placental form glutathione S-transferase) of cell initiation, Satoh et al. (4) have shown that single putative initiated cells (the placental form glutathione S-transferase-positive hepatocytes) and mini-foci consisting of such cells (2-10 cells) predominate in the preneoplastic liver within the first 12 weeks after a single exposure to diethylnitrosamine. Within 1 week after exposure, the e...

Identification problem for stochastic models with application to carcinogenesis, cancer detection and radiation biology

“…Significance of the set Ef stems from the fact that, for O<_t<_T, Yakovlev and Polig (1996), Boucher and Yakovlev (1997), Boucher et al (1998) and Tsodikov and Mtiller (1998) used Y-P model for analysis of real time-to-tumor data that resulted from animal experiments. In particular, Y-P model has explained successfully the inverse dose-rate effect in radiation carcinogenesis (Yakovlev et al, 1977;Yakovlev and Polig, 1996) and allowed estimation of the proportion of initiated cells, which are killed by urethane in mice (Boucher and Yakovlev, 1997;Boucher et al, 1998). The promotion time distribution was assumed to belong to the gamma family with PDF given by Eq.…”

A Multi-stage Model of Adenoma Development

“…Note that the above simpli"ed analysis has implicitly assumed a constant age in the study population; however, if heterogeneity in 134 age were accounted for, a similarly skewed distribution of (t ), for each age t , would still be required to achieve the observed population "ndings. A similar negative binomial distribution of adenoma counts in the population, again due to heterogeneity of the Poisson parameter in individuals, was observed by Boucher & Yakovlev (1997) in their modeling of multiple lung adenomas in mice exposed to a carcinogen.…”

Effects of uracil calculi on cell growth and apoptosis in the BBN‐initiated wistar rat urinary bladder mucosa

“…The complete elimination of initiated cell clones by active cell death could have abolished the efects of initiation [34,35,39,40] in the BBN-treated group. However, the significant higher density of PNH (Table II) and eventual neoplasia development in this group (M3, Table I) indicate that some of the PNH remained, while in the non-initiated mucosa they mostly reverted.…”