The neoplastic transformation of SCID cells by radiation

Severe combined immunodeficiency (SCID) cells are hypersensitive to killing by ionizing radiation because of deregulation of DNA-dependent protein kin ase (DNA-PK) and a concomitant deficiency in the repair of DNA double-stran d breaks. The effect of this condition on the neoplastic transformation of SCID fibroblasts, designated SCID 3T1, has been investigated. The spontaneo us transformation rate was similar to 2 x 10(-5) at early passages and incr eased up to similar to 7 x 10(-3) at later passages. The radiation survival curves of transformed cells had thresholds and therefore appeared to be qu alitatively similar to the survival curves of C3H 10T1/2 mouse fibroblast c ells, but the initial slopes were steeper. In contrast, per unit dose, SCID cells were more sensitive to transformation than 10T1/2 cells. Eight trans formed clones were tested for tumorigenicity, and all produced fibrosarcoma s in athymic nude mice. Properties associated with the tumor suppressor Trp 53 (formerly known as p53) were examined in three of the clones. In these c lones, although Trp53 protein was overexpressed, a lower expression of Cdkn 1a (formerly known as p21, Cip1) protein was observed compared to parental cells. The expression of Trp53 and Cdkn1a and the G(1)-phase arrest (one se t of data on G(1)-phase delay is included as an example) was not induced by ionizing radiation in these transformed clones; each clone carried a point mutation in Trp53. This suggests that the deficiency in the repair of DNA double-strand breaks increased the tumorigenicity and the genomic instabili ty of transformed SCID cells. (C) 1999 by Radiation Research Society.