Evidence for ras gene mutation in 2-amino-3-methylimidazo[4,5-f]quinoline–induced colonic aberrant crypts in the rat

✍ Scribed by Nicholas Tachino; Rick Hayashi; Christina Liew; George Bailey; Roderick Dashwood

• Publisher: John Wiley and Sons
• Year: 1995
• Tongue: English
• Weight: 457 KB
• Volume: 12
• Category: Article
• ISSN: 0899-1987
• DOI: 10.1002/mc.2940120402

✦ Synopsis

Aberrant crypt foci (ACF) are putative preneoplastic lesions that develop after treatment o f animals w i t h colon carcinogens, including cooked-meat heterocyclic amines such as 2-amino-3-methylimidazo[4,5fjquinoline (IQ). Male F344 rats given IQ by gavage o n alternating days f o r 2 w k (130 mg/kg body weight) and killed 12 w k after the final carcinogen dose had an average o f 4.4 ACF/colon and an average of 3.2 crypts/focus. The DNA from these ACF was amplified by t h e polymerase chain reaction and analyzed by 3'-primer mismatch and direct sequencing methods for mutations in t h e Ki-ras proto-oncogene. Of the 37 IQ-induced ACF screened, three contained a GGTjGAT mutation i n codon 12 and one contained a GGC+GCC mutation in codon 13. The approximately 11 % frequency o f mutation in IQ-induced ACF is within t h e range o f previous ACF studies of azoxymethane, which reported a 7-37% incidence o f Ki-ras mutation. These findings suggest that for both compounds, ras mutations occur during early stages of colorectal tumorigenesis. However, while ras mutations can be detected w i t h increasing frequency in azoxymethane-induced adenomas and carcinomas, they are reportedly absent in IQ-induced colon tumors. Thus, f o r IQ and related compounds additional factors (possibly increased cell proliferation) may be important i n the later stages o f colorectal tumorigenesis.