科研之友
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摘要
In addition to being a potent hepatocarcinogen, aflatoxin B-1 (AFB(1)) is a pulmonary carcinogen in experimental animals and epidemiological studies have shown an association between AFB(1) exposure and lung cancer in humans, Since point mutations at codons 12, 13 and 61 of the K-ms protooncogene are often implicated in chemically induced mouse lung tumors and in human lung adenocarcinomas, we undertook an investigation of the role of K-ras activation in AFB(1)-induced pulmonary carcinogenesis, Female AC3F1 (A/J x C3H/HeJ) mice were treated with AFB(1) (150 mg/kg i.p., divided into 24 doses over 8 weeks), and 6-14 months after the completion of dosing mice were killed and pulmonary adenomas and carcinomas removed, Of the 76 AFB(1)-induced lung tumors analyzed by single strand conformation polymorphism (SSCP) and direct sequencing, 75 possessed K-ras codon 12 mutations (46 GTT, 14 GAT, 13 TGT and 2 TTT; normal, GGT) and one had a GGC-->CGC mutation in codon 13, The observation that K-ras mutations occurred only at G:C base pairs is in agreement with N-7-guanine being the primary site of AFB(1)-DNA adduct formation and with guanine residues being targets for AFB(1)-induced oxidative DNA damage via formation of 8-hydroxydeoxyguanosine (8-OHdG). The AFB(1)-specific nature of the observed K-ras mutation spectrum and the fact that 100% of the tumor samples examined contained K-ras mutations is consistent with K-ras activation being an early, critical event in AFB(1)-induced pulmonary carcinogenesis in AC3F1 mice, The parental origin of the observed K-ras mutations was determined by allele-specific PCR amplification of AFB(1)-induced lung tumor DNA followed by SSCP analysis, In the vast majority of tumors (73/76), the mutated K-ras allele was derived from the lung tumor susceptible A/J parent, This finding supports the existence of a link between K-ras and differences in mouse lung tumor susceptibility.
- 出版日期1996-8
