morphologic transformation frequency of m5S adapted mouse embryonic skin cells that had received 20 mGy was about half the spontaneous frequency of 3 × 10−5 observed in nonprimed cells, the adapted cells exposed 5 h later to a challenge dose of 1 Gy were more susceptible to morphologic transformation than the nonadapted cells (Sasaki 1995). These transformation results, however, contrast with results in mouse C3H 10T1/2 cells that were exposed in plateau phase to a challenge dose of 4 Gy 5 h after a priming dose of 100 or 670 mGy (i.e., adapted cells were more resistant to malignant transformation than nonadapted cells; Azzam and others 1994). Furthermore, the priming dose of 100 or 670 mGy caused an increase by a factor of 2–5 in the transformation frequency relative to the frequency of about 3 × 10−4 observed for nonirradiated cells. When the same group of investigators exposed the same C3H 10T1/2 cells in plateau phase to priming doses of 1, 10, or 100 mGy, the neoplastic transformation frequency was lower by a factor of 3–4 than the spontaneous frequency (Azzam and others 1996). The reduction was observed only when the cells were trypsinized and replated 24 h after irradiation for the transformation assay; trypsinization and replating immediately after irradiation did not alter the frequency. Similar results have been reported by Redpath and coworkers (Redpath and Antoniono 1998; Redpath and others 2001): the malignant transformation frequency was reduced by about half when human hybrid cells approaching confluence were trypsinized and replated 24 h after a priming dose of 10 mGy; again, no statistically significant reduction in transformation frequency was observed when the cells were trypsinized and replated immediately after irradiation.
The validity of extrapolating any of the results from in vitro neoplastic transformation systems to malignant transformation in vivo may be questioned for the following reasons. First, the effects associated with variations in time of trypsinization and replating after irradiation must be understood (Schollnberger and others 2002). Second, the measured neoplastic transformation frequency depends on both the density of viable cells plated (Bettega and others 1989) and the number of generations before the cells become confluent (Kennedy and others 1980). Third, when priming doses of 1–100 mGy resulted in a decrease in the neoplastic transformation frequency, the spontaneous transformation frequency was unusually high in one case (Azzam and others 1994), and a Hela X skin fibroblast human hybrid cell system was used in the other (Redpath and Antoniono 1998). Fourth, studies of malignant transformation in immortalized (already-transformed) cell lines may have little relevance to malignant transformation of normal nonimmortalized cells, especially in vivo, where complex interactive processes can occur (Harvey and Levine 1991; Kamijo and others 1997).
For several mammalian cell lines in culture, adaptive responses for cell lethality after doses of 200–600 mGy (Marples and Joiner 1995; Joiner and others 1996; Marples and Skov 1996; Wouters and others 1996; Skov 1999) and for enhanced removal of thymine glycols after a dose of 2 Gy (Le and others 1998) have been observed 4–6 h after a priming dose of 200 mGy. In Chinese hamster V79 cells, the rate of repair of DNA DSBs induced by 1.5 or 5.0 Gy was increased 4 h after a priming dose of 50 mGy (Ikushima and others 1996).
The adaptive responses of mammalian cells described above, at least for cell survival and repair of DNA strand breaks (Robson and others 2000), may be associated in part with the downregulation of a gene DIR1 90 min after doses of 50–1000 mGy. This gene codes for proteins (Robson and others 1997, 1999, 2000) similar to a family of heat shockrelated proteins (HSPs) known as immunophilins with tetrapeptide repeats (TPRs). TPR-containing proteins, such as cell cyclin proteins cdc23, cdc27, and cdc16, have been reported to form complexes in vivo, and the TPR domain is thought to be involved in binding HSP90 and HSP70. Less binding of HSP70 and the induction of other members of the HSP70 family by low doses of radiation (Sadekova and