Transformation of Cells by Alpha Particles in Vitro

Low doses of alpha particles which simulate radon exposure have been used to achieve malignant transformation of cultured cells in studies aimed at measuring their biological effectiveness and estimating carcinogenic hazards. In general, normal diploid cells, with the exception of some hamster embryo cells, have extremely low transformation rates after irradiation. Studies of transformation therefore often use cells such as mouse 3T3 in which genetic changes have already occurred that increase their overall genetic instability and hence their transformability. Although many of these studies generated linear dose-response curves over the dose ranges used (Miller and others 1996; 1995; Brenner and others 1995; Ling and others 1994), some indicated a nonlinear response with greater effectiveness at the lowest doses (Martin and others 1995; Bettega and others 1992). Considerable uncertainty, therefore, still exists about the precise shape of the dose-response relationship for transformation of cells in culture, and by implication, also for carcinogenesis. The results in general do not permit a definitive answer to be obtained for the shape of the dose-response curve at the lowest doses and dose rates, but at the same time there is no compelling evidence to adopt any one particular nonlinear dose-effect relationship. The many and varied biological changes over long time periods that are involved in carcinogenesis, which are discussed in the following sections, indicate that many factors can be expected to influence the shape of the dose-response relationship.

DNA Damage and its Repair—The Caretaker Genes

The gene products responsible for sensing damaged DNA and carrying out repair, euphemistically called the cellular caretakers (Kinzler and Vogelstein 1997), involve a number of enzymatic systems capable of mending single-and double-strand breaks in DNA and excising damaged and mismatched bases. Double-strand breaks are the most important kinds of damage resulting from radon alpha particles. They can be repaired through at least two pathways: homologous recombination (figure 6.2) or nonhomologous recombination (figure 6.3) (Sargent and others 1997). Repair through homologous or nonhomologous recombination involves complex sets of enzymes, which share components with enzymes and gene products associated with the generation of immunoglobulin diversity, such as RAG1 and RAG2 (Melek and others 1998) and with mitotic and meiotic recombination (Jeggo and others 1995; Jeggo 1990).

Most mammalian somatic cells are in the prereplicative, G1, phase of the cell cycle and double-strand break repair appears to involve the nonhomologous, or illegitimate, end-joining reactions (Jeggo and others 1995). In large part, that is because the homologous chromosomes in a diploid G1 nucleus are widely separated, so nonhomologous recombination can occur at about 104 times the efficiency of homologous recombination (Godwin and others 1994; Benjamin and



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