High susceptibility of Scid mice to colon carcinogenesis induced by azoxymethane indicates a possible caretaker role for DNA-dependent protein kinase

Severe combined immunodeficiency (Scid) mice have defects in V(D)J recombin ation and DNA double-strand breaks repair caused by an inherited genetic de fect in the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). S cid mice are highly susceptible to development of T-cell lymphomas, and bec ause of the nature of its association with DNA repair and recombination, DN A-PKcs is considered to belong to the caretaker class of tumor suppressor g enes. In the present study, the susceptibility of Scid mice to colon carcin ogenesis due to administration of azoxymethane (AOM) was investigated. Sign ificantly higher susceptibility in terms of induction of both aberrant cryp t foci (ACFs), putative pre-cancerous lesions of the colon and colon cancer s was observed as compared with the isogenic strain, C.B-17 mice. The incid ences of colon tumors, either adenomas or adenocarcinomas, in Scid and C.B- 17 mice after administration of AOM (10 mg/kg body weight/week) for 6 weeks were 87% (26 of 30) and 50% (15 of 30), respectively, by experimental week 22 (P < 0.01). The multiplicity of colon tumors in Scid mice was also sign ificantly higher than in C.B-17 mice, being 2.2 +/- 1.5 and 0.9 +/- 1.2, re spectively (P < 0.001). The present study clearly demonstrated high suscept ibility of Scid mice to colon carcinogenesis, which might be attributable t o disruption of the caretaker role of DNA-PK in colonic epithelial cells.