mately carcinogenesis (Lane 1992; Kemp and others 1994; White and others 1994; Levine 1997; Lengauer and others 1998). Evidence has been presented that radiation-induced apoptosis can occur via p53-dependent and p53-independent mechanisms (Strasser and others 1994) initiated by damage in the nucleus (Guo and others 1997) or cytoplasm-membrane (Haimovitz-Friedman 1998). This damage results in cells undergoing apoptosis either during interphase without attempting division (Endlich and others 2000), several hours after they have divided a few times (Forrester and others 1999), or during an aberrant mitosis (Endlich and others 2000). The signal transduction pathways (White and Prives 1999) resulting in radiation-induced apoptosis involve the nucleus and cytoplasm with alterations in mitochondrial electron transport (Voehringer and others 2000) and release of cytochrome c from the mitochondria, which initiates caspase cleavage (Finucane and others 1999) and terminates in activation of a nuclease responsible for internucleosomal digestion of DNA (Wyllie 1998).

In accord with the guardian-of-the-genome hypothesis, mouse tumors undergoing apoptosis in a p53-independent manner contained abnormally amplified centrosomes, aneuploidy, and gene amplification (Fukasawa and others 1997). Also, a decrease in radiation-induced apoptosis associated with nonfunctional p53 or expression of Bcl2 correlated with an increase in mutagenesis (Xia and others 1995; Cherbonnel-Lasserre and others 1996; Yu and others 1997). However, the latter correlation might be due not to p53-mediated’s enhancement of radiation-induced apoptosis (Xia and others 1995) but instead to p53-mediated’s suppression of homologous recombination (Sturzbecher and others 1996), which in turn might suppress genomic instability and a hypermutable phenotype. However, there is evidence that radiation-induced genomic instability is independent of p53 expression (Kadhim and others 1996). Furthermore, when the guardian-of-the-genome hypothesis was tested in lymphocyte cultures that were irradiated under different dose-rate and mitogen-treatment conditions, postradiation incubation allowing apoptotic processes to remove damaged cells did not prevent the development of chromosomal instability during long-term cell proliferation over 51–57 days (Holmberg and others 1998). Thus, the relationship between radiation-induced genomic instability, radiation-induced apoptosis, and radiation-induced cancer is uncertain (discussed at length in Chapter 3). Furthermore, radiation-induced genomic instability could not be induced in normal diploid human fibroblasts (Dugan and Bedford 2003) and may be related to confounding in vitro stress factors (Bouffler and others 2001) or to the cells being partially transformed. Finally, as discussed in Chapter 3, it may be that genomic instability plays a more important role in tumor progression than in tumor initiation.

Data are critically needed for the definition of molecular targets and processes responsible for genomic instability in order to define and understand the dose-response relationship for genomic instability and especially why, in some cellular systems, the induction frequency saturates with only about 10–30% of the surviving cells manifesting genomic instability (Little 1998; Limoli and others 1999) (data presented in Table 2-1). It may be that only a certain fraction of the cells, or those in a certain part of the cell cycle, are susceptible to radiation-induced genomic instability. Until the molecular mechanisms responsible for genomic instability and its relationship to carcinogenesis are understood, the extrapolation of dose-response data for genomic instability to radiation-induced cancers in the low-dose range <100 mGy is not warranted.


In a number of mammalian cell lines, cells irradiated in mitosis or late G2 are most susceptible, cells in G1 are intermediate in susceptibility, and cells in middle to late S phase and early G2 are most resistant to the induction of cell lethality, chromosomal aberrations, and mutations (Sinclair and Morton 1963; Terasima and Tolmach 1963; Dewey and others 1970; Burki 1980; Jostes and others 1980; Watanabe and Horikawa 1980; Chuang and Liber 1996; Leonhardt and others 1997). Also, cells irradiated at the G1/S transition are often observed to be more radiosensitive than cells in G1 or S. However, exceptions have been observed, such as little variation in radiosensitivity during the cell cycle (Henderson and others 1982) and greater sensitivity of cells in late S than of cells in G1 (Thompson and Humphrey 1968; Guo and others 1997; Furre and others 1999). Since radioresistance during late S phase has been attributed to error-free repair of DNA DSBs by homologous recombination when sister chromatids have been replicated (Rothkamm and Lobrich 2003; Rothkamm and others 2003), the lack of radioresistance during late S phase in some cell lines may be attributed to their inability to carry out repair by homologous recombination. Those effects have been observed in connection with relatively high acute doses of 1.5–10 Gy (1500-10,000 mGy), but how such variations in radiosensitivity during the cell cycle may affect responses to low doses up to 100 mGy is not known. Also, there are no reports of studies to determine whether there may be variations in radiosensitivity during the cell cycle for induction of genomic instability. However, studies with cell lines have indicated that cells are most susceptible to malignant transformation in vitro when they are irradiated with high-LET radiation or low-energy X-rays in late G2/M (Cao and others 1992, 1993; Miller and others 1992).

The inverse dose-rate effect (Crompton and others 1990; Amundson and Chen 1996), in which cells at first become more radioresistant and then more radiosensitive again as the dose rate of low-LET radiation is decreased below about 1–10 mGy/min, has been attributed to the arrest of cells in a radiosensitive G2 phase of the cycle (Mitchell and others 1979; Furre and others 1999). However, evidence has been

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